Assessing carrier Risk

Assessing carrier Risk

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susan has been found to be a carrier of Tay Sachs. what is the risk that her maternal aunt is also a carrier if we don't know her parents status?

First you have to know that Tay-Sachs disease is an autosomal recessive genetic disorder. Below we will assume that the mutation is at low frequency in the population.

Probability that Susan's maternal grandparents carry the mutation

The probability that Susan's mother carry the mutation is $frac{1}{2}$. The probability that the mutation is present the Susan's maternal grandparents is therefore also $frac{1}{2}$.

Probability that Susan's aunt received the mutation if her parents where carrying it

Now, if the mutation is present in Susan's maternal grandparents in a single copy (which is a consequence of the assumption of the mutation being at low frequency in the population), then the probability that the sister of Susan's mother received this allele is $frac{1}{2}$ too.

Putting these two probabilities together

Putting these together. $frac{1}{2} frac{1}{2} = frac{1}{4}$. The probability is $frac{1}{4}$.

Genetic Disorders

A gene is a small piece of hereditary material called DNA that controls some aspect of a person&rsquos physical makeup or a process in the body. Genes come in pairs.

Chromosomes are the structures inside cells that carry genes. Chromosomes also come in pairs. Most cells have 23 pairs of chromosomes for a total of 46 chromosomes. Sperm and egg cells each have 23 chromosomes. During fertilization, when the egg and sperm join, the two sets of chromosomes come together. In this way, one half of a baby&rsquos genes come from the baby&rsquos mother and one half come from the baby&rsquos father.

Your baby&rsquos sex is determined by sex chromosomes. There are two sex chromosomes: X and Y. Egg cells only contain an X chromosome. Sperm cells can carry an X or a Y. A combination of XX results in a girl and XY results in a boy.

Genetic disorders may be caused by problems with either chromosomes or genes.

A chromosome disorder is caused by problems with chromosomes. Most children with chromosome disorders have physical defects and some have intellectual disabilities.

Having missing or extra chromosomes is a condition called aneuploidy. The risk of having a child with an aneuploidy increases as a woman ages.

Trisomy is the most common aneuploidy. In trisomy, there is an extra chromosome. A common trisomy is Down syndrome (trisomy 21). Other trisomies include Patau syndrome (trisomy 13) and Edwards syndrome (trisomy 18). Monosomy is another type of aneuploidy in which there is a missing chromosome. A common monosomy is Turner syndrome, in which a female has a missing or damaged X chromosome.

An inherited disorder is caused by a faulty gene that can be passed from parent to child. Faulty genes can occur on any of the chromosomes. There are autosomal dominant disorders, autosomal recessive disorders, and sex-linked disorders.

An autosomal dominant disorder is caused by just one faulty gene from either parent. &ldquoAutosomal&rdquo means that the defective gene is located on any of the chromosomes that are not the sex chromosomes (X or Y). If one parent has the gene, each child of the couple has a 50 percent chance of inheriting the disorder. An example of an autosomal dominant disorder is Huntington disease.

Autosomal recessive disorders only happen when both parents carry the gene. An example of an autosomal recessive disorder is cystic fibrosis (CF).

A carrier of a recessive disorder is a person who carries one copy of a gene that works incorrectly and one that works normally. A carrier may not have symptoms of the disorder or may have only mild symptoms.

If both parents are carriers of an abnormal gene, there is a 25 percent chance that the child will get the abnormal gene from each parent and will have the disorder. There is a 50 percent chance that the child will be a carrier of the disorder&mdashjust like the carrier parents. If only one parent is a carrier, there is a 50 percent chance that the child will be a carrier of the disorder.

Sex-linked disorders are caused by defective genes on the sex chromosomes. An example of a sex-linked disorder is hemophilia. This disease is caused by a faulty gene on the X chromosome.

Multifactorial disorders are caused by a combination of factors. Some factors are genetic and some are not. A few of these disorders can be detected during pregnancy.

Most babies with birth defects are born to couples without risk factors. But the risk of birth defects is higher when certain factors are present. This is why screening for birth defects begins by assessing your risk factors, such as whether

you have a genetic disorder

you have a child with a genetic disorder

there is a family history of a genetic disorder

Some genetic disorders are more common in certain ethnic groups.

A genetic counselor has special training in genetics. A genetic counselor will study your family health history and may recommend you have physical exams or tests with your obstetrician&ndashgynecologist (ob-gyn). Using the test results, the counselor will assess your baby&rsquos risk of having a problem, discuss your options, and talk about any concerns you may have.

Screening tests assess the risk that a baby will be born with a specific birth defect or genetic disorder. Diagnostic tests can detect if a specific birth defect or genetic disorder is present in the fetus.

Screening tests include blood tests that measure the level of certain substances in the mother&rsquos blood combined with an ultrasound exam. These tests assess the risk that a baby will have Down syndrome, other trisomies, or neural tube defects (NTDs).

There also is cell-free DNA screening. Cell-free DNA is the small amount of DNA that is released from the placenta into a pregnant woman&rsquos bloodstream. The cell-free DNA in a sample of a woman&rsquos blood can be screened for Down syndrome, other trisomies, and problems with the number of sex chromosomes.

See Prenatal Genetic Screening Tests to learn more about these tests.

There are no risks to the fetus with any of these screening tests.

Carrier testing is a type of screening that can show if a person carries a gene for an inherited disorder.

Carrier testing often is recommended for people with a family history of a genetic disorder or people from certain races or ethnic groups who are at increased risk of having a child with a specific genetic disorder. CF screening and spinal muscular atrophy (SMA) screening are offered to all women of reproductive age because CF and SMA are the most common genetic disorders.

Carrier testing can be done before or during pregnancy. See Carrier Screening to learn more about prepregnancy carrier testing.

Diagnostic tests may be recommended if a screening test shows an increased risk of a birth defect. Diagnostic testing also is offered as a first choice to all pregnant women, even those who do not have risk factors. Diagnostic tests can detect if a specific birth defect or genetic disorder is present.

Diagnostic tests are done on cells from the fetus obtained through amniocentesis, chorionic villus sampling (CVS), or, rarely, fetal blood sampling. The chromosomes and genes in the cells are analyzed using different techniques to diagnose certain inherited defects and many chromosomal defects. See Prenatal Genetic Diagnostic Tests to learn more.

Diagnostic tests carry risks, including an increased risk of pregnancy loss.

Your ob-gyn or a genetic counselor can discuss all of the testing options with you and help you decide based on your risk factors.

Whether you want to be tested is a personal choice. Some couples would rather not know if they are at risk or whether their child will have a disorder. Others want to know in advance. Knowing beforehand gives you time to prepare for having a child with a disorder and to organize the medical care that your child may need. You also may have the option of ending the pregnancy.

Amniocentesis: A procedure in which amniotic fluid and cells are taken from the uterus for testing. The procedure uses a needle to withdraw fluid and cells from the sac that holds the fetus.

Aneuploidy: Having an abnormal number of chromosomes.

Autosomal Dominant Disorders: Genetic disorders caused by one defective gene. The defective gene is located on one of the chromosomes that is not a sex chromosome.

Autosomal Recessive Disorders: Genetic disorders caused by two defective genes, one inherited from each parent. The defective genes are located on one of the pairs of chromosomes that are not the sex chromosomes.

Birth Defects: Physical problems that are present at birth.

Carrier: A person who shows no signs of a disorder but could pass the gene to his or her children.

Cell-Free DNA: DNA from the placenta that moves freely in a pregnant woman&rsquos blood. Analysis of this DNA can be done as a noninvasive prenatal screening test.

Cells: The smallest units of a structure in the body. Cells are the building blocks for all parts of the body.

Chorionic Villus Sampling (CVS): A procedure in which a small sample of cells is taken from the placenta and tested.

Chromosomes: Structures that are located inside each cell in the body. They contain the genes that determine a person&rsquos physical makeup.

Cystic Fibrosis (CF): An inherited disorder that causes problems with breathing and digestion.

Diagnostic Tests: Tests that look for a disease or cause of a disease.

DNA: The genetic material that is passed down from parent to child. DNA is packaged in structures called chromosomes.

Down Syndrome (Trisomy 21): A genetic disorder that causes abnormal features of the face and body, medical problems such as heart defects, and mental disability. Most cases of Down syndrome are caused by an extra chromosome 21 (trisomy 21).

Edwards Syndrome (Trisomy 18): A genetic condition that causes serious problems. It causes a small head, heart defects, and deafness.

Egg: The female reproductive cell produced in and released from the ovaries. Also called the ovum.

Fertilization: A multistep process that joins the egg and the sperm.

Fetus: The stage of human development beyond 8 completed weeks after fertilization.

Gene: A segment of DNA that contains instructions for the development of a person&rsquos physical traits and control of the processes in the body. The gene is the basic unit of heredity and can be passed from parent to child.

Genetic Counselor: A health care professional with special training in genetics who can provide expert advice about genetic disorders and prenatal testing.

Hemophilia: A disorder caused by a mutation on the X chromosome. Affected people are usually males who lack a substance in the blood that helps clotting. People with hemophilia are at risk of severe bleeding from even minor injuries.

Huntington Disease: An disorder that causes loss of control of body movements and mental function.

Monosomy: A condition in which there is a missing chromosome.

Neural Tube Defects (NTDs): Birth defects that result from a problem in development of the brain, spinal cord, or their coverings.

Obstetrician&ndashGynecologist (Ob-Gyn): A doctor with special training and education in women&rsquos health.

Patau Syndrome (Trisomy 13): A genetic condition that causes serious problems. It involves the heart and brain, cleft lip and palate, and extra fingers and toes.

Placenta: An organ that provides nutrients to and takes waste away from the fetus.

Prenatal Care: A program of care for a pregnant woman before the birth of her baby.

Screening Tests: Tests that look for possible signs of disease in people who do not have signs or symptoms.

Sex-Linked Disorders: Genetic disorders caused by a change in a gene located on the sex chromosomes.

Sperm: A cell produced in the male testicles that can fertilize a female egg.

Spinal Muscular Atrophy (SMA): An inherited disorder that causes wasting of the muscles and severe weakness. SMA is the leading genetic cause of death in infants.

Trisomy: A problem where there is an extra chromosome.

Turner Syndrome: A problem that affects women when there is a missing or damaged X chromosome. This syndrome causes a webbed neck, short height, and heart problems.

Ultrasound Exam: A test in which sound waves are used to examine inner parts of the body. During pregnancy, ultrasound can be used to check the fetus.

There is a test to learn if a person has one of the three genetic mutations associated with early-onset Alzheimer's disease, which occurs between a person’s 30s and mid-60s.

If someone has a family history of early-onset Alzheimer's, he or she should talk with a doctor about getting tested.

A doctor may suggest meeting first with a genetic counselor. This type of counselor helps people learn the risk of getting genetic conditions. They also help people make decisions about testing and what comes next.


Carrier screening is a term used to describe genetic testing that is performed on an individual who does not have any overt phenotype for a genetic disorder but may have one variant allele within a gene(s) associated with a diagnosis. Information about genetic carrier screening should be provided to every pregnant woman. After counseling, a patient may decline any or all screening. Carrier screening and counseling ideally should be performed before pregnancy because this enables couples to learn about their reproductive risk and consider the most complete range of reproductive options, including whether or not to become pregnant and whether to use advanced reproductive technologies such as preimplantation genetic diagnosis or use of donor gametes. Knowledge during pregnancy allows patients to consider prenatal diagnosis and pregnancy management options in the event of an affected fetus.

If an individual is found to be a carrier for a specific condition, the individual’s reproductive partner should be offered testing in order to receive informed genetic counseling about potential reproductive outcomes. Concurrent screening of the patient and her partner is suggested if there are time constraints for decisions about prenatal diagnostic evaluation. If both partners are found to be carriers of a genetic condition, genetic counseling should be offered. Prenatal diagnosis and advanced reproductive technologies to decrease the risk of an affected offspring should be discussed. Prenatal carrier screening does not replace newborn screening, nor does newborn screening replace the potential value of prenatal carrier screening.

When an individual is found to be a carrier for a genetic condition, the individual’s relatives are at risk of carrying the same mutation. The patient should be encouraged to inform his or her relatives of the risk and the availability of carrier screening. The obstetrician–gynecologist or other health care provider should not disclose this information without permission from the patient.

It is important to obtain the family history of the patient and, if possible, her partner as a screening tool for inherited risk. The family history should include the ethnic background of family members as well as any known consanguinity (a union between two individuals who are second cousins or closer in family relationship) 1*. Individuals with a positive family history of a genetic condition should be offered carrier screening for the specific condition and may benefit from genetic counseling. Ideally, information on the specific mutation will be available to aid testing and counseling.

Carrier screening for a particular condition generally should be performed only once in a person’s lifetime, and the results should be documented in the patient’s health record. Because of the rapid evolution of genetic testing, additional mutations may be included in newer screening panels. The decision to rescreen a patient should be undertaken only with the guidance of a genetics professional who can best assess the incremental benefit of repeat testing for additional mutations.

Although several different strategies for screening are available and reviewed in Committee Opinion No. 690,Carrier Screening in the Age of Genomic Medicine, this document seeks to provide information about the different conditions for which a patient may seek prepregnancy carrier screening. If a patient requests carrier screening for a particular condition for which testing is readily available and which reasonably would be considered in another screening strategy, the requested test should be offered to her (regardless of ethnicity and family history) after counseling on the risks, benefits, and limitations of screening. The cost of carrier screening for an individual condition may be higher than the cost of testing through commercially available expanded carrier screening panels. When selecting a carrier screening approach, the cost of each option to the patient and the health care system should be considered.

What follows is a detailed discussion of some of the more common genetic conditions for which carrier screening is recommended in at least some segments of the population. The different sections collect topics that had previously been discussed in separate Committee Opinions to show how the aforementioned general principles are used and reflected in carrier screening for specific genetic conditions.


Autism is a lifelong neuropsychiatric condition first apparent during early development that is characterized by social and communication deficits and by repetitive behaviors and restricted interests. The severity and variety of symptomatic behaviors, impairments, and abilities that autistic individuals show is vast, leading to the formal conceptualization of autism as a spectrum (autism spectrum disorder, ASD) [1]. ASDs also differ by sex, with a striking and consistent male bias in prevalence [2, 3].

In recent years, interest in investigating sex differences in the autistic phenotype and exploring a potential need for sex-differential diagnostic criteria has grown more widespread [4, 5]. At the same time, research findings and public discourse have challenged the magnitude of the male bias in prevalence [6–10], and genetics studies have demonstrated patterns of risk variation that are consistent with a protective effect against the ASD phenotype in females [11–21]. Work to identify the sex-differential factor(s) responsible for this protection has returned several potential leads, but the key factor(s) involved remains unknown, and the molecular, cellular, and/or neurodevelopmental pathway(s) by which these factors impact risk are not currently understood. Given the strong impact of sex on ASD prevalence and/or presentation, understanding the points of interaction between sex-differential factors and ASD etiological pathways is likely to reveal critical aspects of ASD biology that may provide effective therapeutic targets. More and continued attention to these questions, particularly with input from the sex differences research community, is warranted to begin to make concrete sense of the ways that sex-differential neurodevelopment and brain function modulate neuropsychiatric risk. Here, I aim to summarize the current state of research findings on sex differences in ASD prevalence, phenotype, and risk mechanisms, as well as to highlight gaps in our current understanding that are likely to benefit from input from the sex differences research community.

Autism prevalence is male-biased

The most striking sex difference in ASD is its prevalence, as approximately four times as many males have a diagnosis of ASD as females [2]. This 4:1 male:female ratio is a commonly cited statistic that represents a consensus across epidemiological studies conducted in different countries, at different times, and using different iterations of diagnostic criteria on an individual study level, the degree of male skew can vary widely. Though recent in-depth prevalence studies have tended to report smaller male biases than the 4:1 estimate [6, 8, 10], ASD-diagnosed males consistently predominate across these and earlier epidemiological surveys [2, 3], making sex-biased prevalence one of the most temporally and geographically stable features of ASDs.

At face value, this pattern of disparate prevalence suggests the action of sex-differential risk factors for ASD that act to either increase males’ risk and/or protect females. Just a few decades ago, as our conceptualization of ASD shifted from the domain of psychoanalysis to neuropsychiatry and genetics, an assumption that sex-differential risk factors were also biological in nature followed suit [22, 23]. More broadly, this paradigm shift and the dismissal of parenting style as the cause of ASD (so-called “refrigerator mothers” [24, 25]) revealed gaps in our knowledge of autism that researchers have aimed to fill. For much of the field, top priority questions included characterizing the behaviorally defined autistic phenotype in neuroscientific terms, particularly from the cognitive neuroscience [26, 27] and structural/functional neuroanatomical perspectives [28–31], with the intention to leverage these descriptions to discover ASD’s underlying causes. During this time, a handful of research groups published studies that compared males and females with ASD on the presentation and severity of their autism symptoms [32–35] or on neuroanatomical features [36, 37]. However for a majority of analyses, despite the male skew in ASD’s prevalence, sex was most frequently considered a variable to control for, not an aspect of risk to investigate in its own right. Often, to reduce experimental variability, characterization studies of autistic behavior, cognition, neuroimaging, and neuroanatomy only included male participants with ASD.

Still, despite more widespread focus on characterizing the autistic phenotype and its cause(s), the hypothesis that some aspect of male and/or female biology modulates ASD risk remained. Several research groups proposed the involvement of general sexually dimorphic factors such as X-linkage [38, 39], imprinting [40, 41], and sex steroid hormone levels [42]. However, another, non-mutually exclusive possibility is that females are affected by ASD at higher rates than previously thought, but that they are not being diagnosed. If this scenario were true, it would require a careful reexamination of the ASD phenotype, our understanding of which is based on the study of majority male cohorts, as well as our assumptions about sex-differential risk and protection for ASD.

Since males have predominated in studies of the features and phenotype of ASD, it can be argued that diagnostic criteria and instruments for ASD preferentially describe what ASD looks like in a male. The manifestation of ASD in females, then, may not appear to meet diagnostic criteria, which would lead to a smaller number of females being diagnosed and an apparent male bias in prevalence. To better understand the female’s autistic phenotype, studying diagnosed females is informative, but results must be interpreted in light of the caveat that these are the females who are identifiable under potentially male-biased diagnostic criteria. Additional work is required to unpack the possibility and consequences of missed diagnoses in females.

Ideally, such work should explore both (1) phenotypic traits in non-diagnosed females and (2) long-term outcomes. In particular, evaluation of females without ASD diagnoses who meet at least a subset of current defining criteria and/or who have other neuropsychiatric or neurodevelopmental diagnoses may be informative for identifying potential gaps in diagnostic criteria where females are likely to fall short. Following such individuals longitudinally will also be required to determine if quality of life (e.g., lack of social engagement) and/or achievement outcomes (e.g., employment status relative to cognitive ability) are negatively impacted in these females. Findings of poor outcomes would indicate that these individuals stand to benefit from diagnosis and the services and therapies available to autistic patients. This would also motivate revision of the diagnostic criteria for ASD in order to better identify these females.

Detailed analyses of ASD prevalence have certainly hinted at the possibility of skewed diagnoses in males compared with females. For example, studies comparing autistic individuals across a range of intellectual ability have shown that the male bias is as high as 9:1 among cases with intelligence quotient (IQ) in the normal-to-high range (frequently termed “high functioning”) but as low as 1.6:1 among cases with intellectual disability [43–45]. Though intellectual ability or disability is not part of the diagnostic criteria for ASD, if intellectual ability is thought to reflect overall phenotypic severity, this pattern of fewer females among autistic patients with normal-to-high IQ could suggest that females are largely protected against all but the most penetrant risk factors.

Alternatively, it might be the case that females must present with comorbid intellectual disability or a clear syndrome in order to be evaluated for, or receive a diagnosis of, ASD. Given that our current understanding of ASD is based on a body of research from predominantly male cases, it has been suggested that either the diagnostic criteria for ASD, or clinicians’, educators’, and parents’ understanding of these criteria, do not accurately reflect how females present with ASD [4]. In this case, females’ ASD symptoms may tend to go unnoticed, particularly for high-functioning individuals with strong verbal skills, unless other troubling behaviors or difficulties prompt an in-depth evaluation [46]. A study of children with high levels of autistic traits who either met, or fell just short of, the diagnostic criteria for ASD found patterns consistent with this hypothesis: diagnosed girls were more likely than diagnosed boys to score significantly below average on a test of verbal and nonverbal cognitive ability and significantly above average on a measure of behavioral difficulties [47]. Similarly, a study of the distribution of quantitative ASD traits in families enrolled in a voluntary national registry found that a significantly smaller proportion of females than males with Social Responsiveness Scale (SRS) scores in the top 1% received ASD diagnoses from community professionals [48]. To determine the factors driving females’ versus males’ diagnoses, though, additional data will be required regarding the circumstances of each child’s diagnosis, including parents’ early concerns or motivation for seeking evaluation. Additionally, as the authors of the study of children above and below the diagnostic threshold caution, these findings could plausibly result from either gender-biased diagnoses or from protective mechanisms in females.

Some degree of diagnostic bias is also evident in studies of ASD prevalence, as different methodological approaches uncover different male:female ratios among affected individuals. One common approach for estimating prevalence of a condition is to query existing records of diagnoses or symptoms. These records come from professionals in the community and incorporate these professionals’ interpretations and applications of the ASD diagnostic criteria (Fig. 1c). Prevalence studies using this record-based approach tend to report male:female ratios in the range of approximately 3:1 to 5:1 [2, 3, 49–54], the magnitude that is frequently cited. A second, more intensive approach is to screen a large sample of the general population for ASD traits, without a priori assumptions about which individuals are most likely to be affected (Fig. 1a). For example, instead of evaluating only children in special education classrooms for ASD, two recent large-scale studies in South Korea and Finland screened all school-age children in their selected samples [6, 8]. This unguided screening approach identified far more girls meeting criteria for ASD than record-mining studies typically do, with a 2.5:1 male:female prevalence in South Korea [6] and between 1.7:1 and 2.3:1 male:female ratio for different subsets of the autism spectrum in Finland [8]. In places where ASD screening is widespread, integrated into standard care, and diagnoses are recorded in government or private registries (Fig. 1b), similarly low male biases in prevalence have been reported, including 2.8:1 in Toyota, Japan [9], and 2.3:1 in the Stockholm Youth Cohort in Sweden [10].

Approaches used to estimate ASD prevalence and male:female ratio. Different approaches may identify different overall, and sex-specific, prevalence rates. a Screening populations in full, irrespective of existing diagnostic status. b Analysis of records in existing, standardized registries. c Collating and/or sampling and interpreting available records from scholastic or medical records. d Baby siblings studies, where researchers prospectively monitor the younger siblings of autistic children for recurrence of ASD and other traits of interest. Filled figures represent individuals with ASD

On a smaller scale, another approach that allows researchers to thoroughly screen a sample for ASD without relying on records of community diagnoses involves prospective observation of the younger siblings of autistic individuals, who are at substantially elevated risk for ASD than the general population this is often called a “baby sibs” study (Fig. 1d). One such study of Canadian children reported relative odds of ASD in male versus female siblings of autistic probands of only 1.65 [7]. An earlier study of children from 12 sites in the USA and Canada [55] and the largest study of these high-risk siblings to date [56] reported somewhat stronger male skews, with a relative risk of 2.8 and odds ratio of 3.18 (male versus female), respectively. However, the male biases in these studies are still on the lower end of reported sex ratios, together indicating that the high surveillance of these siblings, from investigators and parents, tends to identify a greater number of affected females.

Considered with full population and systematic screens, and in contrast to studies of diagnostic records, these patterns suggest that some number of affected females are not being diagnosed under the current system. One possible explanation for this is that, as described above, the current diagnostic criteria for ASD do not accurately describe the female presentation of ASD. Not only is this mismatch between criteria and presentation in females likely to impact estimates of ASD prevalence, but it likely has affected the ascertainment of samples and cohorts for studies as well. Therefore, this potential ascertainment bias toward males and strongly impacted females must be considered when interpreting reports of sex differences in ASD. It is still encouraging though that broad-based searches, in contrast to work on clinical records, identify a larger fraction of affected females using standard screening tools. This could suggest that it is not necessarily the diagnostic criteria themselves that are grossly male-specific. Instead, it could be that physicians’, teachers’, and parents’ interpretation of ASD symptoms in females may drive or exacerbate the male skew in prevalence.

If the results from unbiased population screens are any indication, we may find that increased awareness of the possibility of ASD in girls will subsequently facilitate an increase in the identification of affected individuals. For example, the Autism and Developmental Disabilities Monitoring Network (ADDM) of the Centers for Disease Control (CDC) in the USA periodically reports on ASD prevalence across multiple sites nationwide, and these reports show an increase in ASD prevalence over time [49, 57, 58]. A breakdown of ASD rates across time shows that a large contribution to this increase comes from diagnoses in school-aged males with milder ASD symptoms both in the USA [51] and in a Swedish cohort [10]. Study of incidence rates between 1995 and 2010 from the Danish Psychiatric Central Research Registry uncovered a comparable pattern of increasing incidence in older individuals (school age and above) and in milder subtypes of the autism spectrum including Asperger’s syndrome and Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) [59]. Increases in these specific subpopulations may reflect increased awareness of more subtle presentations of ASD, without comorbid intellectual disability.

Similarly, as awareness and understanding of ASD in females grow, we may begin to see increased rates of ASD in females reported by these prevalence-monitoring surveys. In fact, results from the study of incidence rates in Denmark demonstrate this very pattern, with increasing diagnoses in females leading to a reduction in the male/female ratio from 5.1 in 1995 to 3.1 in 2010 this reduced male bias was most striking for diagnoses of Asperger’s syndrome (8.4 to 3.0) and PDD-NOS (5.7 to 2.8) [59]. Additionally, results from the National Health Interview Study (NHIS) in the USA collected in 2014 show a 3:1 male/female ratio, down from 4.5:1 from the same survey in 2011–2013 [52]. Of note, the NHIS changed the order and format of its questions about ASD and developmental delay (DD) between the 2011–2013 and 2014 surveys such that the item on ASD was moved from a 10-condition checklist to a standalone question. In this new format, ASD status was queried before DD status. This formatting change may have contributed to the observed increase in ASD prevalence overall, from 1.25% in 2011–2013 to 2.24% in 2014, and a reciprocal decline in DD prevalence from 4.84% in 2011–2013 to 3.57% in 2014. Interestingly, in contrast to this overall decline in DD prevalence, the proportion of females with DD increased (34.6% in 2011–2013 to 36.7% in 2014), suggesting that males were mainly responsible for diagnostic substitutions between ASD and DD in the two survey periods. Therefore, the increase in the proportion of female children with ASD (18.3% in 2011–2013 to 25% in 2014) may also be at least partially attributable to the format change, but it is also possible that the observed increase in prevalence reflects increasing recognition of ASD in females. This recognition can only be accelerated by ongoing work to characterize females’ presentation and experience of ASD.

The recognition of shortcomings in our understanding of ASD in girls has sparked recent interest in studying autistic females, to better characterize the presentation of their symptoms, their cognitive and neuroanatomical phenotype, and how they differ from boys with ASD [4]. Thus far, studies of very young children have failed to identify sex differences in ASD symptoms among affected individuals [60, 61]. Outside of ASD-specific traits, one such study did also observe higher scores in affected females on the Daily Living Skills Subscale of the Vineland Adaptive Behavior Scales (VABS) [61]. Another study of male and female adults with ASD found no sex differences in retrospective reports of childhood autism traits, in keeping with the pattern above, but sex differences in social communication were apparent in adulthood [62]. Specifically, despite reports of equivalent ASD traits during childhood, adult females with ASD showed significantly fewer social communication difficulties than adult males during clinical evaluation (Autism Diagnostic Observation Schedule, ADOS).

Autistic females in this sample also self-reported higher scores on a measure of ASD symptoms compared with males, suggesting disconnect between their observed and experienced social behavior. This sort of behavior is consistent with the concept of “camouflaging” one’s ASD symptoms by making conscious, concerted effort to learn and emulate social norms. The application of this rote knowledge of social behavior may effectively hide an innate lack of skill in certain interactions, but the frequently monumental effort required to do this often goes unnoticed. In fact, though autistic females may have similar trouble with social communication as autistic boys do early in life, females may have greater social motivation and desire to be liked and engaged with her peers [62, 63] this motivation may be what drives high functioning females in particular to camouflage their difficulties. It is unclear to what extent this desire and ability to compensate for social challenges by rote learning and performance of normative behaviors may be truly compensatory or protective against diagnosis in females, versus an exhausting and distressing burden for affected females to bear. It will be important to identify these girls who may escape diagnosis by engaging in camouflaging behavior and to determine their outcomes over time and the support they may need.

In addition to camouflaging behavior in high functioning females, studies of older children and adults with ASD are finding that autistic females tend to show reduced levels of restricted interests and repetitive behaviors compared with males. A large study of individuals from 970 families enrolled in the Autism Genome Project (AGP) observed lower repetitive behavior scores from the Autism Diagnostic Interview-Revised (ADI-R) in females [64]. A breakdown of the items contributing to the repetitive behavior scores further showed that this sex difference was driven by a reduction in females’ restricted interests but not of repetitive sensorimotor behaviors. Phenotypic characterization of 2418 cases in the Simons Simplex Collection (SSC) also revealed a similar pattern, with females showing reduced restricted interests [65]. Importantly, as female cases in the SSC are more likely to have cognitive impairment than male cases, IQ did not mediate this sex difference. Such reduction in restricted interests is also apparent in recent work, including a study of Australian children [63] and a study of autistic case data from the National Database for Autism Research (NDAR) and the Autism Brain Imaging Data Exchange Consortium (ABIDE) [66].

An alternative possibility is that females have just as many, or just as intense, restricted interests as males, but that these interests occur in different domains. In other words, autistic children’s interests may differ in much the same ways that the interests of male and female neurotypical children differ from one another, on average: while males with ASD might fixate on transit schedules or maps, females might fixate on horses or popular performers [67]. If diagnostic criteria more accurately represent the male phenotype, this may allow females’ restricted interests, as well as other phenotypic traits, to fly under the diagnostic radar [68, 69].

All together, a tendency toward increased social motivation, ability to consciously mask social impairment, and reduced or potentially non-prototypical restricted interests may cause affected females to not be evaluated or diagnosed [4, 70]. As characterization work continues and awareness of the possibility of ASD in females grows, we may find that diagnostic criteria and instruments need to be adjusted to better capture those girls who are struggling and would benefit from behavioral interventions and support. For example, the incorporation of female-typical exemplars into ASD diagnostic criteria and screening instruments (as has already been implemented in the Autism Spectrum Screening Questionnaire-Revised, ASSQ-REV [71]) might facilitate clinicians’ recognition of females’ symptoms. It is important to note, however, that the extent to which this differential presentation and missing diagnoses in females may account for the sex bias in ASD prevalence is not known, and a male bias may very well persist even with increased awareness and adjusted diagnostic criteria.

Evidence for a female protective effect in ASD

Though ongoing work to better characterize and identify autistic females is required to quantify the true risk-modulatory impact of sex, current data, including general population screens [6, 8–10] and high-risk sibling studies [7, 55, 56], continue to show male-biased prevalence. Furthermore, sex differences in the presentation and experience of ASD symptoms are also consistent with the idea that ASD risk factors have qualitatively, as well as quantitatively, different impact in males and females.

One theoretical model for the relationship between sex and ASD risk is derived from a multiple threshold liability model and is commonly referred to in the field as a “female protective effect” (FPE Fig. 2a) [46, 72]. This model posits that risk for ASD is quantitative, that it follows a distribution in the general population, and that females are protected from the impact of this risk. This female-specific or female-preferential protection leads to a reduced prevalence compared with males. One assumption of this model is of course that, when faced with risk factors, females are protected from becoming autistic. However, as introduced above, it may also be that female-protective mechanisms modulate the effects of risk factors on females’ phenotypes such that they are not diagnosed (i.e., females are protected from diagnosis of ASD). Awareness of this possibility is critical and much additional work is required to address it, but for the purposes of exploring current work on the FPE model as it is commonly interpreted, we will accept the assumption that females are protected from ASD itself. Given this, under the FPE model, the threshold of risk burden that females must carry (e.g., deleterious genetic variants) or experience (e.g., environmental exposures), before their neurodevelopment is impacted to the degree that they present with a diagnosable autistic phenotype, is greater than for males.

Sex-differential ASD risk can be represented by a multiple-threshold liability/FPE model. a Under a multiple threshold liability/female-protective effect (FPE) model, risk or liability for ASD is quantitative and distributed in the population, and males and females have different minimum liability thresholds that are sufficient to lead to an ASD diagnosis. The tail of the distribution filled in gray indicates those individuals in the population with diagnosed ASD. b A closer look at the region marked with a green, dotted box in a. A key prediction from the FPE model is that among diagnosed individuals, females will have greater ASD liability than males. A secondary prediction is that non-diagnosed females may carry, or be exposed to, relatively high ASD liability but they do not present symptoms that meet criteria for diagnosis mothers of autistic children may include such females. c Examples of sex-differential biological factors proposed to contribute to males’ and females’ shifted liability thresholds and differential risk for ASD. Figure adapted from Werling and Geschwind [46]

A key premise of the FPE model is that the factors responsible for the distribution of ASD risk are the same in males and females. It is then hypothesized that female-protective mechanisms act on this common distribution of liability to modulate the impact of risk factors on neurodevelopment and behavior in a sex-differential manner. This is in contrast to a scenario where a subset of risk factors increases ASD risk only in males, which could also lead to sex-differential prevalence. Currently, the full spectrum of risk factors for autism is not understood, but it is well accepted that genetic variation plays a significant role [13–15, 20, 21, 73–78].

With regard to this genetic component of ASD risk, we would expect males and females to be equally likely to carry risk-contributing genetic variants in the same set of genes or at the same loci. In recent years, risk gene discovery work using whole exome sequencing of autism families has dramatically increased the number of genes that can be significantly associated with ASD risk. Apart from ASD-associated monogenic syndromes caused by X chromosome mutations, such as fragile X syndrome, which affects mostly males, and Rett syndrome, which is lethal to males and therefore affects mostly females, these ASD risk loci are predominantly autosomal [15]. Furthermore, analysis of disruptive variants in the 65 genes currently associated with ASD risk demonstrates that these variants are randomly distributed across male and female probands, a pattern that does not support the existence of sex-specific genetic risk factors and is consistent with the premise of a common underlying distribution of genetic risk for ASD in males and females [15].

An important point to make regarding ASD-associated genes and risk loci is that, although the relative risk of disruptive variants in these genes and loci is high, most are not likely to be fully penetrant. This is most clearly seen in studies characterizing the phenotypes of patients and family members who carry copy number variations (CNVs) associated with ASD risk such as 22q11.2 or 16p11.2 deletions. Carriers of the 16p11.2 deletion sometimes do, and sometimes do not, meet diagnostic criteria for ASD, but as a group, carriers show decreased IQ as compared with the general population and with non-carrier family members [79–81], demonstrating that these variants are associated with alterations in neural function in carriers. This and other evidence suggests that genetic background is critical for determining the impact of risk factors, with the additive effects of common variants likely playing a sizeable role in ASD risk [73]. Therefore, it is likely that the same disruptive genetic variant will have different effects on individuals with different genetic backgrounds, pushing individuals over the phenotypic threshold to diagnosable ASD in some cases but not in others [82].

Analogous to the distribution of genetic risk across families and individuals, the behaviors and cognitive patterns that define ASD have also been shown to follow a quantitative distribution in general population samples from the USA [83, 84] and the UK [85, 86]. Idiosyncrasies in social communication and repetitive behaviors or restricted interests are not limited to individuals with ASD, and sub-diagnostic presentation of ASD-like traits, particularly in non-diagnosed family members of ASD cases, are common this is sometimes referred to as the broader autism phenotype (BAP) [87]. Characterization of quantitative traits associated with ASD has shown that unaffected females in the general population score lower on measures of ASD traits [12, 85, 88] (i.e., more social, more communicative, and less likely to show restricted interests). This basic sex difference, whether driven by innate neurobiology, socialization, or both, may mean that strong risk variants are less likely to push females’ phenotypes into the diagnosable range. However as stated above, in patient cohorts as they are currently ascertained, known ASD-associated genetic variants are randomly distributed between males and females with ASD [15]. Again, this suggests that there is a common set of key genes and loci that modulate ASD risk in both sexes, but that females, on average across the population, are buffered from their effects.

The FPE model also makes several key predictions about the properties and effects of ASD risk factors, each of which can be tested to support or refute the existence of female-differential protection. First and foremost, the FPE model predicts that among diagnosed individuals, females carry or experience greater risk than diagnosed males, on average (Fig. 2b). Given that ASD is highly heritable [48, 55, 89–92], if autistic females carry greater inherited genetic risk than autistic males, then one would expect to observe higher recurrence rates for ASD among the family members of autistic females than males. This pattern of proband sex-mediated recurrence is called the Carter Effect [93], and it has been remarkably difficult to demonstrate in ASD.

Specifically, multiple prospective high-risk sibling studies have failed to find a significant effect of proband sex on ASD recurrence rates in later-born siblings [7, 55]. Though these study designs include families who are likely to be loaded for genetic risk, a relatively small number of families were identified that had both female probands and subsequent affected children, suggesting that these studies may be underpowered to observe the Carter Effect. Interestingly, larger studies on the scale of national registries in Denmark [92] and Sweden [91], which utilized records from over 1.5 million and 2 million children, respectively, also failed to find significantly increased recurrence risk in families with diagnosed females. Both studies tested all combinations of older and younger sibling sex for differences in recurrence rates between these pairings. The study of Swedish children found higher relative recurrence risk in younger siblings of diagnosed females, though this effect did not reach statistical significance. Given the observation of wide confidence intervals around recurrence risk estimates in each group of sex-stratified sibling pairs, the authors of the Danish study cautioned that even their large, non-ascertained cohort included a fairly small number of diagnosed girls and therefore may also be poorly powered to detect significant differences between these groups [92].

In contrast to these reports on high risk and population samples, a study of two population twin cohorts in which ASD traits were measured on a quantitative scale showed significantly higher autistic trait scores in the co-twins of affected females than in the co-twins of affected males [12]. “Affected” here was defined by a score on a quantitative autistic trait measure above the 90th sex-specific percentile, as opposed to a standard diagnosis. This sex-specific quantitative approach for identifying probands is particularly useful, as it has the potential to reduce ascertainment biases against affected females that may result from male-focused diagnostic criteria and screening instruments. Additionally, a study of exclusively multiplex families from the Autism Genetic Resource Exchange (AGRE) cohort reported significantly greater recurrence rates in the later-born children of “female-containing” families (at least one female proband) [94]. In these families from AGRE, recurrence rates were highest for younger male siblings of female probands, suggesting that not only do autistic females carry more penetrant heritable risk for ASD, but that males may be more vulnerable to the inherited risk background that these females share with their siblings.

At present, these disparate results have not been fully reconciled. One reasonable possibility is that differences in genetic architecture between the cohorts used in the studies are responsible for the different patterns observed. Specifically, the Carter Effect is dependent on a penetrant contribution from inherited genetic risk variants that are shared between siblings. Individuals from multiplex families are more likely to carry these inherited risk variants than are simplex, or single incidence families, who show enrichment for risk variants observed only in the child that are not inherited from either parent (de novo variation) [14]. Estimates from a volunteer registry and from high-risk sibling studies suggest that only as many as 10–27% of families with an autistic child are multiplex [7, 48, 55, 56]. Therefore, population cohorts and study samples that are not filtered by family type are likely testing children from largely simplex families with primarily de novo genetic risk. Since these children are less likely to share these penetrant genetic risk variants with their siblings, this reduces the power to observe significant increases in recurrence in diagnosed females’ siblings.

Bias against the identification of female cases by male-tailored diagnostic instruments may also contribute to this loss of power. If diagnosed females represent a subset of all affected females, and if the key genetic risk variants carried by diagnosed females are more frequently de novo than inherited (as compared with diagnosed males), this would reduce the observed recurrence in siblings of female probands. It may be that affected females who currently escape diagnosis are more likely to carry inherited, or common, genetic risk profiles, and identifying these females may improve power to observe significantly higher recurrence in siblings of female versus male probands. However, despite these potential caveats regarding statistical power, the fact that studies of millions of children from national registries do not observe a Carter Effect remains a conundrum.

As discussed above, observing a Carter Effect in a sex-biased condition requires inference about the underlying genetic risk. Today, we can observe most genetic variants directly, including single nucleotide variants (SNVs) and large CNVs or structural variants. In the genetic risk space, then, we can directly test the same prediction of the FPE model that is associated with the Carter Effect: do autistic females carry greater risk than autistic males?

In fact, risk gene discovery studies of de novo variants in simplex families do find direct evidence of greater risk burden in diagnosed females at the genetic level. Early work on CNVs in families from the SSC observed a trend toward higher frequency of de novo CNVs in autistic females compared with males [13, 14]. These same studies both also found that females’ de novo CNVs impact a significantly greater number of genes than those in affected males. A recent analysis of CNVs in the combined SSC and Autism Sequencing Consortium samples was sufficiently powered to observe a statistically significant increase in both the number of genes hit by CNVs and in the frequency of de novo CNVs in females [15].

Early exome sequencing studies on the same cohort reported an analogous trend, with a higher rate of de novo SNVs overall [16], or exclusively for nonsense [17] or gene disrupting SNVs [18], in female cases. This sex difference, however, did not reach statistical significance in any case. In contrast, a subsequent study of de novo indels in SSC cases did observe a significantly increased rate of de novo frameshift indels in females [19]. Later analysis of whole exome sequencing in a larger, combined sample of 16 constituent ASD sample sets was able to find a significantly increased rate of de novo loss-of-function SNVs in genes associated with ASD risk in females [20]. A simultaneous publication on whole-exome sequencing of the complete SSC further reported that the set of genes disrupted by de novo SNVs in females overlaps significantly with the genes disrupted in affected males with low, but not high, IQ [21], demonstrating the high impact of the risk variants that female cases tend to carry.

A potential concern with these findings of greater genetic risk in diagnosed females is the impact of IQ on females’ ascertainment in study cohorts. As discussed, females with cognitive impairment may be more likely to be diagnosed with ASD than those with normal-to-high IQ. Irrespective of sex, ASD cases with low IQ are more likely to carry an identifiable genetic risk variant (e.g., de novo loss-of-function SNV, dnLoF, or de novo CNV, dnCNV) than cases with higher IQ [15, 21]. Therefore, it may be that the enrichment of disruptive genetic variation seen in female cases is actually a byproduct of the average lower IQ in ascertained female cases as compared with male cases. Work characterizing the phenotypic traits of probands in the SSC has demonstrated that the female probands in this cohort have a lower IQ than the male probands, and that the smaller proportion of females with high IQ (IQ ≥ 80) drives this difference [65]. However, this difference in the distribution of IQ in female probands does not appear to fully account for the observed sex difference in de novo risk variant rate. In the analysis of dnCNVs and dnLoF in the combined SSC and ASC cohorts, the presence of a dnLoF or dnCNV was associated with an 8-point decrease in nonverbal IQ (NVIQ) in males and an 18-point decrease in females as compared with sex-matched probands lacking dnLoF or dnCNV [15]. Similarly, both female and male probands with NVIQ below the cohort median of 89 had a significantly higher rate of dnLoF or dnCNVs than sex-matched probands with NVIQ above the median score (females, 2.2-fold enrichment males 1.6-fold enrichment). Splitting NVIQ into smaller bins (≤50, 51–70, 71–90, 91–110, 111–130, >130) showed that, although the differences did not reach statistical significance, in every NVIQ bin, a greater percentage of female than male probands had a dnLoF or dnCNV. These patterns suggest that the association between female sex and a higher rate of de novo risk variants cannot be fully explained by the greater frequency of ascertained females with low IQ in these samples. Taken together, the results of these genetic analyses are in keeping with the prediction from the FPE model that females with autism are subject to greater risk loads than autistic males.

A second prediction of the FPE model mirrors the first: if affected females have greater ASD liability than males, then unaffected females just below the diagnostic threshold are likely to have greater ASD liability than unaffected males as well (Fig. 2b). Put another way, if females are protected from ASD risk, then there are likely to be females in the population who are subject to bona fide ASD risk factors, but who do not present with a diagnosable autistic phenotype. Since the genetic variant space is still the best defined and testable source of ASD risk, screening the general population for ASD risk variants would be one way to identify these high-risk, protected females. However, due to reduced fecundity in ASD [95], interpretable risk variants for ASD are rare, making the required sample size for adequate power in this study design prohibitively high. As sequencing costs drop and commercial and medical genetic testing become more commonplace, such a study may become feasible.

Analogous to the studies of infant siblings of autistic probands, another option is to look at samples of females at high risk for carrying ASD-associated genetic variants. The mothers of autistic cases may represent one such group. Though studies of de novo variants have had great success for identifying ASD risk genes and loci, ASD’s high heritability demonstrates that inherited variation also plays a role in ASD risk. Since mothers of autistic cases are female and therefore experience putative female protective mechanisms that allow them to withstand the impact of ASD risk variants, it has been hypothesized that inherited risk variants in probands are more likely to have come from the mother than the father [72, 96]. A study of transmitted autosomal CNVs in a cohort of individuals with neurodevelopmental disorders and an independent sample of 762 ASD families from the SSC observed exactly this pattern: large, disruptive CNVs over 400 kb in size were more frequently maternally than paternally inherited in both cohorts [11]. More recent analysis of over 2000 families from the SSC corroborates this finding, reporting a significant enrichment in probands compared with siblings for maternally transmitted nonsense SNVs and small CNVs under 100 kb in size [97]. Additionally, a study of copy number genotypes in ASD cases and family members from several sample collections found that mothers in the AGRE cohort carried CNVs that impacted a greater number of genes than fathers’ CNVs, and mothers in the SSC carried a significantly greater number of CNVs than fathers [98].

Given the above support for the FPE model from observed patterns of genetic variation in ASD patients and families, the next aim in the field should be to determine the root cause and mechanism(s) responsible for such a female protective effect. To accomplish this will require both targeted approaches, like the Autism Sisters Project launched by the Autism Science Foundation which will collect data from unaffected sisters of autistic siblings [99], as well as general investigation of the differences between typical male and female neurodevelopment and neural functions.

Proposed biological risk and protective factors for ASD

Over the years, several preliminary theories for ASD’s sex-differential risk have been proposed and explored. The first, most straightforward hypothesis was that, like many conditions that only affect males, ASD is X-linked [100]. In this scenario, ASD is caused by a mutation in a gene(s) on the X chromosome, and females are protected by their second X chromosome, which carries redundant and likely functional copies of the mutated risk gene(s). In the early days of genetic research in ASD when it was known that ASD showed high heritability but the contributing genetic loci were largely unknown, X-linkage seemed a likely hypothesis. However, due in large part to the rapid and dramatic success of de novo variant detection and association approaches, we now know that while there are several ASD-associated genes on the X chromosome, the majority of risk genes are autosomal [15]. Loss-of-function variants in the fraction of risk genes on the X chromosome are not sufficiently common to account for the magnitude of the sex bias in ASD prevalence.

A second hypothesis also invokes the X chromosome, proposing that a single gene on the X that is imprinted and paternally expressed is responsible for females’ protection. Since only females have a paternal X chromosome, males do not express this gene and therefore do not experience its protective properties [40]. This hypothesis is based on observations from a study of individuals with monosomic Turner’s syndrome, which reported that females whose single X chromosome was inherited from their father (45, X p ) had greater social and executive functioning skills than females with only a maternal X (45, X m ) [41]. Skuse and colleagues propose that this difference indicates the existence of a locus on the X chromosome that promotes social cognition, and that this locus is only, or largely, expressed from the paternal X. By mapping paternal X chromosome partial deletions in 8 patients with partial monosomy, the researchers concluded that this imprinted, pro-social genetic locus must originate from the q arm of the X, or near the centromere on the p arm. Though intriguing, this locus has not been further resolved, and no single, imprinted, protective gene has been identified to date for ASD.

A third, genetics-based hypothesis proposes that protection in females is conferred by variation at a single genetic locus, whether on the X chromosome or an autosome. This hypothesis was suggested in response to work characterizing quantitative ASD traits in multiplex families these studies found that scores from the SRS followed a nearly normal distribution across affected and unaffected males, but that females’ scores showed a bimodal distribution split between diagnosed and non-diagnosed individuals [48, 101]. Since in this case, diagnosed and non-diagnosed children are siblings who are assumed to share 50% of a common genetic background, this female-specific bimodal distribution is consistent with the effects of a single, binary locus that can protect carrier females from ASD. However, a sufficiently powered genome-wide association study of 317,574 independent SNPs in 208 female cases and 151 unrelated female controls from AGRE families failed to identify any SNPs significantly associated with ASD status in females [102]. This suggests that the source of the FPE, if it is rooted in genetics, is likely to be polygenic and possibly driven by multiple rare variants instead of a single common variant.

Beyond genetic variation, other proposed mechanisms feature a role for sex steroid hormones during neurodevelopment. The best known is the extreme male brain (EMB) theory, which was proposed by Simon Baron-Cohen and conceptualizes the cognitive-behavioral phenotype of ASD as an amplification of male-typical interests, skills, and behaviors [42]. The theory suggests that there are two key, orthogonal dimensions of sex-differential ability: empathizing, or a drive to perceive and respond appropriately to the thoughts, intentions, and emotions of others, which is more pronounced in females (on average), and systemizing, or a drive to observe and understand the structure and rules of orderly phenomena (math, physics, maps, calendars, mechanics, etc.), which is more pronounced in males. Individuals with autism, then, are those who are especially high systemizers but especially low empathizers.

Since typically developing males, in general, fall closer to the autistic phenotype on these scales than females, Baron-Cohen proposed that testosterone exposure during fetal development may contribute to ASD risk, particularly for autistic girls [42]. Insofar as natural sex differences in testosterone levels may be responsible for amplifying risk in males and/or dialing down risk in females, this hypothesis is consistent with the FPE model. Common thinking about the FPE is that there exists some female-specific, or at least female-preferential, factor or mechanism that actively buffers neurodevelopment against the impact of risk factors. It is important to remember that, while its shorthand name references protection in females, the FPE model is at its root a multiple threshold liability model, and the patterns and predictions of the FPE model are also entirely compatible with the involvement of male-specific risk factors. Such risk factors may operate in lieu of, or in addition to, female-specific protective factors.

Only once a specific mechanism is implicated will we know which is the driving force behind setting males’ and females’ liability thresholds. Until then, whether one considers male-specific risk or female-specific protective factors to be key depends on the baseline of one’s frame of reference. For example, it is straightforward to say that females tend to require more deleterious genetic variants before they present with ASD, and therefore females are protected against lesser variants. This assumes though that the scale of variants’ deleteriousness is based on their impact in males, since females are framed as coping with variants that would typically (i.e., in males) be penetrant. If the deleteriousness of risk variants is instead normalized to their impact in females, then one would reinterpret the sex-differential risk variant distribution to mean that it is males who require less deleterious genetic variants to present with ASD. In this case, the pertinent question is not what mechanism protects females, but what factor or mechanism sensitizes males to this class of less penetrant (in females) risk variants? Since neither males nor females as a group represent the prototypical human, it is not clear which frame of reference is the “correct” one or the one most likely to facilitate discovery of the mechanisms that mediate sex-differential ASD risk. For now, research in this area should consider the possibilities of both female-specific protective factors and male-specific risk factors when designing and interpreting studies.

In their subsequent work to investigate the biology behind the EMB theory, Baron-Cohen and colleagues have performed several studies of the relationship between fetal testosterone levels and phenotypes later in life. In a sample of 235 majority non-autistic children whose mothers had undergone amniocentesis during gestation, the authors observed a significant positive relationship between fetal testosterone levels and quantitative measures of ASD traits [103]. If we conceptualize autistic traits as a continuum in the population that is set by an underlying distribution of exposure to risk factors, then this pattern suggests that testosterone exposure is associated with a shift in the trait distribution toward a diagnosable phenotype. Another study examined the relationship between gestational testosterone levels and neuroanatomy by looking for brain regions with differential gray matter volume in 28 young boys (age 8–11) with different fetal testosterone levels [104]. Here, they observed that regions with testosterone-associated gray matter volume also showed sex-differential gray matter volume in 217 age-matched children with structural imaging data in the National Institutes of Health Pediatric Magnetic Resonance Imaging Data Repository. Specifically, gray matter volume in the right temporoparietal junction/posterior superior temporal sulcus (RTPJ/pSTS) was greater in males and also positively associated with the tested males’ fetal testosterone levels, while gray matter in the planum temporale/parietal operculum (PT/PO) and the posterior lateral orbitofrontal cortex (plOFC) was greater in females and negatively associated with males’ fetal testosterone. Though not directly tied to ASD traits, these findings demonstrate that the putative effects of testosterone exposure align with typical sex differences and that these effects are evident in neuroanatomy. A similar study in girls, particularly those with high testosterone levels (e.g., congenital adrenal hyperplasia patients), would be informative.

Most recently, by making use of national registry data from Denmark, Baron-Cohen and colleagues were able to test for a relationship between fetal testosterone levels and ASD status in the same individuals [105]. By linking biobanked amniotic fluid samples from the gestation of children in the Danish Historic Birth Cohort to records of their later diagnoses in the Danish Psychiatric Central Register, the authors applied a case-control design to test for differences in gestational levels of several hormones: testosterone, progesterone, 17α-hydroxy-progesterone, androstenedione, and cortisol. Hormone levels were compared between affected and unaffected male children only, as there were insufficient numbers of affected females with banked amniotic samples to perform a comparable analysis in female children. All five hormones, including testosterone, showed mean elevation in affected male children as compared to unaffected males, providing the first significant association between fetal testosterone and ASD. Though the distributions of testosterone and the other tested hormones overlap substantially between cases and controls, it is noteworthy that differences in case and control group means are apparent within a sample of exclusively male children. This suggests that testosterone levels, as opposed to a binary-like relative presence or absence of testosterone, may have a positive relationship with ASD risk. Such a binary model may be an oversimplification, but it is the case that the level of testosterone that a fetus is exposed to during gestation differs substantially by sex, as males’ differentiated testes secrete testosterone to drive further sexual differentiation of the body and brain toward male morphology. Therefore, an alternative hypothesis about the relationship between testosterone and ASD risk is that exposure to testosterone above a certain level (e.g., a level sufficient for morphological masculinization) acts to increase risk, and conversely, exposure below this level has no impact on risk. However, as stated above, the findings from this study suggest that relative levels of testosterone, even within males, are associated with ASD risk. A comparable analysis of females, when available, will be informative for further evaluating these possibilities.

Also, though the testosterone findings from this analysis are compelling, the elevation of related hormones in addition to testosterone suggests that the pathways that translate early hormone exposure to an autistic phenotype are multifactorial. That cortisol was one of the elevated hormones suggests that these ASD risk pathways may involve stress responses. Whether the elevation in cortisol results from a response to stress or is a consequence of increased testosterone or other confounding phenomena is not known, and will require further investigation.

What also remains unclear from each of the above studies of fetal testosterone and later phenotypes is whether fetal testosterone acts to skew risk toward males simply because males are more likely to be exposed to higher levels of testosterone or instead whether fetal testosterone preferentially impacts males because females are protected from its effects via some other process. This question is perhaps best addressed by studying the relationship between testosterone levels and ASD-associated phenotypes specifically in females, to determine how testosterone exposure impacts this presumably protected group. Individuals with congenital adrenal hyperplasia (CAH) have a deficiency in the enzyme 21-hydroxylase which causes their adrenal glands to produce abnormally high levels of testosterone, providing a unique population in which to examine the effects of testosterone in females. One study of 34 women with CAH and 24 of their unaffected relatives found that females with CAH scored significantly higher on the Autism Spectrum Quotient (AQ), a self-report questionnaire that measures individuals’ autistic traits [106]. CAH females’ scores were comparable to unaffected males, while males with (N = 26) and without (N = 25) CAH showed no difference in AQ scores. Despite the small sample size, this finding suggests that, insofar as prenatal exposure to testosterone above a certain threshold shifts individuals’ autistic trait measures toward the diagnosable end of the distribution, females are similarly impacted by testosterone exposure as males.

That testosterone may also affect females’ ASD risk is further supported by reports linking ASD and polycystic ovary syndrome (PCOS), another condition associated with increased testosterone production. In one study, a higher than expected proportion of females with ASD (N = 415) reported symptoms of steroid hormone irregularities such as irregular menstrual cycles or precocious puberty, that are frequently associated with PCOS [107]. A more recent analysis of national registry data from Sweden found that children of women with PCOS are at higher risk for ASD (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.34–1.88), and that this risk is further exacerbated by comorbid obesity in mothers, a condition known to be both a contributor and consequence of high androgen levels in PCOS patients (OR 2.13, CI 1.46–3.10) [108]. This study also showed that the magnitude of this increase in risk to offspring of mothers with PCOS was equivalent for male and female children, as compared to children of the same sex whose mothers did not have PCOS (males OR 1.60, CI 1.31–1.94 females OR 1.58, CI 1.14–2.20). Together, these findings are consistent with the hypothesis that elevated exposure to testosterone and/or irregular steroidogenic activity is associated with elevated ASD risk. They also suggest that the source of this exposure may vary, including exposure to the mother’s hormonal state during gestation, or as a result of a comorbid steroidogenic abnormality in the female ASD patient herself.

Under the EMB/fetal testosterone model, the patterns observed in these studies are consistent with the idea that females’ protection and males’ risk is rooted in population-level differences between females’ and males’ exposures to testosterone. Additional research may uncover important nuances in the pathways linking testosterone to ASD neurodevelopment, possibly including androgen receptor regulation in specific cell types or brain regions, or the local generation of androgens from other steroid molecules by populations of brain cells. However, it remains possible that exposure to testosterone, whether systemic or locally generated in the brain, contributes strongly to ASD risk. For example, testosterone may very well initiate or maintain neurodevelopmental processes that steer the brain toward more autistic-like circuitry and function. Therefore, several of the next questions for the field to address involve the specifics of neurodevelopment downstream from testosterone exposure. This, of course, becomes the general study of sexual differentiation and dimorphism of the brain, which is not by any means uniquely relevant to ASD. To better understand sex-biased ASD risk, though, the key will be to determine where, when, and how sex differences in the brain intersect with ASD’s etiological pathways. This endeavor would benefit greatly from the applied expertise of sex differences researchers.

Investigation of molecular and cellular mechanisms linking sex-differential biology and ASD risk

Thus far, the question of how sex-differential neurobiology interacts with the etiological pathways in ASD at a mechanistic level has only been preliminarily addressed. One group of investigators set out to implicate specific molecular pathways in ASD pathophysiology by looking for gene expression differences in lymphoblastoid cell lines (LCLs) from males with ASD and their unaffected brothers. Genes differentially expressed between siblings showed significant enrichment for genes involved in cholesterol metabolism and androgen biosynthesis pathways [109], and a subset of the affected cases also showed higher testosterone levels than their brothers, together supporting patterns of elevated steroidogenic activity in ASD.

Complementary analyses of differential methylation in LCLs and gene expression in the ASD brain identified two candidate genes with elevated methylation in ASD and decreased expression in the ASD frontal cortex and cerebellum [110]. One of these genes, retinoic acid-related orphan receptor alpha (RORA), is a transcription factor that is involved in a sex steroid hormone expression regulatory pathway. Specifically, estrogen and androgen receptor binding sites have been found upstream from RORA’s transcription start site and its expression in SH-SY5Y cell culture increases in response to treatment with 17-β estradiol (E2) but decreases in response to dihydrotestosterone (DHT) [111]. RORA binding sites have been identified upstream from CYP19A1 (aromatase), an enzyme that converts testosterone to estradiol, and there is a positive relationship between RORA and CYP19A1 expression, including coordinate reduction of both RORA and CYP19A1 protein in post mortem ASD frontal cortex [111]. Several other regulatory targets of RORA show sex-differential expression levels, and the correlation between RORA and target expression is stronger in males [112], further linking RORA to sex-differential biology. It remains unclear as to whether RORA acts as a primary risk factor for ASD, or whether its dysregulation in ASD is a downstream consequence of altered androgen or estrogen expression. Regardless, this deep characterization approach for investigating ASD-associated molecular pathways will be important for understanding the mechanistic links between ASD and sex-differential biology.

Genome-wide screening approaches will also be important for identifying additional molecular and cellular pathways involved in ASD and sex-differential biology. Unlike candidate gene approaches, genome-wide methods such as exome, genome, or even RNA sequencing have the potential to provide an unbiased survey of the key biological processes involved in ASD. A recent study applied such a tactic, using a genome-wide survey of sex-differentially expressed (sex-DE) genes in the adult and fetal human post mortem cortex, and results from exome sequencing and coexpression network analyses in ASD, to determine how risk genes or related pathways overlap with sex differences in the human brain [113]. If ASD-associated risk genes are sex-differentially expressed in the typically developing human brain, then variants in these genes might lead to different outcomes in males and females such that a greater proportion of variant-carrying males meet diagnostic criteria for ASD. Alternatively, if ASD-associated risk genes are not sex-differentially expressed, then the risk-modulatory effect of sex must operate on other, interacting molecular pathways. Combining results from genome-wide gene expression studies in ASD and control samples may facilitate the identification of these key molecular points of intersection.

In fact, this analysis did not find any evidence for sex-differential expression of ASD-associated risk genes as a class. Instead, the results showed significant overlap between genes with higher expression in males [113] and genes up-regulated in post mortem autistic brain relative to similarly male-skewed control groups [114, 115]. These ASD-up-regulated genes that show enrichment for higher expression in males are coexpression modules associated with functions related to the immune system in the brain, microglia, and astrocytes. Genes with higher expression in males also showed significant enrichment for sets of astrocyte and microglial marker genes derived from independent experiments [116, 117]. Together, these patterns suggest that some aspects of ASD biology, particularly functioning of the immune system and/or glial cells, parallels the differences between typical male and female neurobiology (Fig. 3). Currently, evidence exists in the literature for sex differences in rodents in astrocyte morphology in the hypothalamus [118–120], hypothalamic astrocyte responses to estradiol [121, 122], and in microglial colonization of the brain [123, 124], and these new gene expression data from humans indicate that a similar sex difference may exist in the human cortex as well.

Microglia and/or astrocytes may have a role in ASD pathophysiology and sex-differential biology. ASD risk genes, when disrupted, affect processes in the developing brain such as molecular pathways, cellular functions, and neural circuits (thick green arrows), which subsequently lead to an ASD phenotype. Sex-differential regulatory mechanisms also influence different, and possibly overlapping, processes (thick purple arrows). A gene recent gene expression analysis by Werling and colleagues (2016) demonstrated that genes associated with the functions of microglia and/or astrocytes show higher expression in males (versus females) as well as higher expression in the ASD brain (versus controls), suggesting that these cell types may contribute to both typical sex differences in the brain and ASD pathophysiology. This is one potential pathway that may contribute to ASD’s male-biased prevalence

Looking forward, given the small number of independent samples in each tested data set, it is imperative that this observation of male-skewed expression of astrocyte and microglial genes be replicated in independent, well-powered data sets. If this pattern does reflect biological truth, it opens up the next round of questions regarding the cause of this sex-differential gene expression and its mechanistic relationship with ASD etiological pathways. For example, is the higher expression of genes associated with astrocyte and microglial functions in males the result of sex differences in cortical cell type composition, i.e., do males have a greater number of microglia than females? Do males’ astrocytes and microglia express marker genes at higher levels? If so, what sex-differential regulatory mechanisms are responsible for directing these differences in expression levels? Or, are other cell types in males more likely to show ectopic expression of astrocyte and microglial marker genes?

Given the overlap at this particular functional and cellular junction with gene expression patterns observed in ASD brain, the answers to these questions are likely to be pertinent for understanding ASD risk and for identifying potential therapeutic targets. Rigorous experimental work to pursue this line of questioning or others that may emerge from high-throughput, bioinformatics approaches would certainly not only be relevant to ASD but would also advance our knowledge of the sex-differential development, structure, and function of the human brain more generally. Concerted and collaborative efforts between ASD clinicians, epidemiologists, geneticists, and neuroscientists with expertise in sex differences will be required to facilitate progress toward better understanding of the processes governing sex-differential neurobiology, ASD biology, and the ways in which they intersect with each other to increase risk for, or protect against, ASD.

Steps you can take

If you know you have an abnormal gene linked to breast cancer, there are lifestyle choices you can make to keep your risk as low it can be:

These are just a few steps you can take. Review the links on the left side of this page for more options.

Along with these lifestyle choices, there are other risk-reduction options for women at high risk because of abnormal genetics.

Hormonal therapy medicines: Two SERMs (selective estrogen receptor modulators) and two aromatase inhibitors have been shown to reduce the risk of developing hormone-receptor-positive breast cancer in women at high risk.

  • Tamoxifen has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in both postmenopausal and premenopausal women at high risk. Certain medicines may interfere with tamoxifen's protective effects. Visit the Tamoxifen page to learn more.
  • Evista (chemical name: raloxifene) has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in postmenopausal women. Visit the Evista page to learn more.
  • Aromasin (chemical name: exemestane), an aromatase inhibitor, has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in postmenopausal women at high risk. Aromasin isn’t approved by the FDA for this use, but doctors may consider it a good alternative to tamoxifen or Evista. In 2013, the American Society of Clinical Oncology (ASCO) released new guidelines on using hormonal therapy medicines to reduce breast cancer risk in high-risk women. These guidelines recommend that doctors talk to high-risk postmenopausal women about using Aromasin to reduce risk. ASCO is a national organization of oncologists and other cancer care providers. ASCO guidelines give doctors recommendations for treatments that are supported by much credible research and experience. Visit the Aromasin page for more information.
  • Arimidex (chemical name: anastrozole), also an aromatase inhibitor, has been shown to reduce the risk of first-time hormone-receptor-positive breast cancer in postmenopausal women at high risk. Like Aromasin, Arimidex isn’t approved by the FDA for this use, but doctors may consider it a good alternative to tamoxifen, Evista, or Aromasin. Visit the Arimidex page for more information.

Hormonal therapy medicines do not reduce the risk of hormone-receptor-negative breast cancer.

More frequent screening: If you're at high risk because of an abnormal breast cancer gene, you and your doctor will develop a screening plan tailored to your unique situation. You may start being screened when you're younger than 40. In addition to the recommended screening guidelines for women at average risk, a screening plan for a woman at high risk may include:

  • a monthly breast self-exam
  • a yearly breast exam by your doctor
  • a digital mammogram every year starting at age 30 or younger
  • an MRI scan every year starting at age 30 or younger

Women with an abnormal breast cancer gene need to be screened twice a year because they have a much higher risk of cancer developing in the time between yearly screenings. For example, the Memorial Sloan-Kettering Cancer Center in New York, NY recommends that women with an abnormal BRCA1 or BRCA2 gene have both a digital mammogram and an MRI scan each year, about 6 months apart (for example, a mammogram in December and an MRI in June).

A breast ultrasound is another powerful tool that can help detect breast cancer in women with an abnormal breast cancer gene. This test does not take the place of digital mammography and MRI scanning.

Talk to your doctor, radiologist, and genetic counselor about developing a specialized program for early detection that addresses your breast cancer risk, meets your individual needs, and gives you peace of mind.

Protective surgery: Removing the healthy breasts and ovaries — called prophylactic surgery ("prophylactic" means "protective") — are very aggressive, irreversible risk-reduction options that some women with an abnormal BRCA1 or BRCA2 gene choose.

Prophylactic breast surgery may be able to reduce a woman's risk of developing breast cancer by as much as 97%. The surgery removes nearly all of the breast tissue, so there are very few breast cells left behind that could develop into a cancer.

Women with an abnormal BRCA1 or BRCA2 gene may reduce their risk of breast cancer by about 50% by having prophylactic ovary and fallopian tube removal (salpingo-oophorectomy) before menopause. Removing the ovaries lowers the risk of breast cancer because the ovaries are the main source of estrogen in a premenopausal woman’s body. Removing the ovaries doesn’t reduce the risk of breast cancer in postmenopausal women because fat and muscle tissue are the main producers of estrogen in these women. Prophylactic removal of both ovaries and fallopian tubes reduces the risk of ovarian cancer in women at any age, before or after menopause.

Research also has shown that women with an abnormal BRCA1 or BRCA2 gene who have prophylactic ovary removal have better survival if they eventually are diagnosed with breast or ovarian cancer.

The benefit of prophylactic surgeries is usually counted one year at a time. That’s why the younger you are at the time of surgery, the larger the potential benefit, and the older you are, the lower the benefit. Also, as you get older you’re more likely to develop other medical conditions that affect how long you live, such as diabetes and heart disease.

Of course, each woman's situation is unique. Talk to your doctor about your personal level of risk and how best to manage it.

It's important to remember that no procedure — not even removing both healthy breasts and ovaries at a young age — totally eliminates the risk of cancer. There is still a small risk that cancer can develop in the areas where the breasts used to be. Close follow-up is necessary, even after prophylactic surgery.

Prophylactic surgery decisions require a great deal of thought, patience, and discussion with your doctors, genetic counselor, and family over time — together with a tremendous amount of courage. Take the time you need to consider these options and make decisions that feel comfortable to you.

For more information, visit the Prophylactic Mastectomy and Prophylactic Ovary Removal pages.

This content was developed with contributions from the following experts:

Christina Nixon, MS, LCGC, a licensed certified genetic counselor with the Cancer Risk Assessment and Genetics Program at Main Line Health

Peggy Cottrell, MS, LCGC, a licensed certified genetic counselor at Holy Name Medical Center, and the Genetics Program Coordinator at Sharsheret

Think Pink, Live Green: A Step-by-Step Guide to Reducing Your Risk of Breast Cancer teaches you the biology of breast development and how modern life affects breast cancer risk. Download the PDF of the booklet to learn 31 risk-reducing steps you can take today.

Assessing Genetic Risks: Implications for Health and Social Policy (1994)

Each new genetic test that is developed raises serious issues for medicine, public health, and social policy regarding the circumstances under which the test should be used, how the test is implemented, and what uses are made of its results. Should people be allowed to choose or refuse the test, or should it be mandatory, as newborn screening is in some states? Should people be able to control access to the results of their tests? If test results are released to third parties such as employers or insurers, what protections should be in place to ensure that people are not treated unfairly because of their genotype?

The answers to these questions depend in part on the significance given to four important ethical and legal principles: autonomy, confidentiality, privacy, and equity. A review of the meaning of those concepts and how they are currently protected by the law provides a starting point for the development of recommendations on the degree of control people should have in deciding whether to undergo genetic testing and what uses should be made of the results. The task is a pressing one. In a 1992 national probability survey of the public, sponsored by the March of Dimes, 38 percent of respondents said that new types of genetic testing should be stopped altogether until the privacy issues are settled. 1

This chapter reviews some of the conflicts that will arise in the research and clinical settings, and suggests general principles that should be the starting point for policy analyses in this evolving field.

Since many of the references in this chapter are legal citations, its references appear in legal style as numbered end notes.



Ethical Analysis

Autonomy can be defined as self-determination, self-rule, or self-governance. Autonomous agents or actions presuppose some capacity of reasoning, deciding, and willing. Moral, social, and legal norms establish obligations to respect autonomous agents and their choices. Respect for personal autonomy implies that agents have the right or power to be self-governing and self-directing, without outside control. In the context of genetic testing and screening, respect for autonomy refers to the right of persons to make an informed, independent judgment about whether they wish to be tested and then whether they wish to know the details of the outcome of the testing. Autonomy is also the right of the individual to control his or her destiny, with or without reliance on genetic information, and to avoid interference by others with important life decisions, whether these are based on genetic information or other factors. Respect for autonomy also implies the right of persons to control the future use of genetic material submitted for analysis for a specific purpose (including when the genetic material itself and the information derived from that material may be stored for future analysis, such as in a DNA bank or registry file).

Even though respect for autonomy is centrally important in our society, it is not absolute. It can be overridden in some circumstances, for example, to prevent serious harm to others, as is the case in mandatory newborn screening for phenylketonuria (PKU) and hypothyroidism.

Legal Issues

The legal concept of autonomy serves as the basis for numerous decisions protecting a person's bodily integrity. In particular, cases have held that competent adults have the right to choose whether or not to undergo medical interventions. 2 Before people make such a choice, they have a right to be informed of facts that might be material to their decision, 3 such as the nature of their condition and its prognosis, 4 the potential risks and benefits of a proposed test or treatment, 5 and the alternatives to the proposed intervention. 6 In the genetics context, health care providers have been held liable for not providing the information that a genetic test is available. 7

People also have a right to be informed about and to control the subsequent use of tissue that has been removed from their bodies. 8 There is some leeway under the federal regulations governing research involving human subjects for researchers to undertake subsequent research on blood samples provided for genetic tests (as in the newborn screening context) as long as the samples are anon-

ymous and as long as the subsequent use was not anticipated at the time the sample was collected. 9 If the additional test was anticipated at the time the sample was collected, informed consent for that use should be obtained prior to the collection of the original sample.

Such an approach is thought appropriate to avert conflicts of interest, such as a physician/researcher suggesting that a patient undergo a particular test when the researcher actually wanted the tissue for the researcher's own additional use in a research or commercial project. In such a situation, the patient's autonomy is compromised even if the sample is used anonymously in the subsequent use. A report from the Office of Technology Assessment similarly stressed the importance of knowledge and consent:

The consent of the patient is required to remove blood or tissue from his or her body, and also to perform tests, but it is important that the patient be informed of all the tests which are done and that a concern for the privacy of the patient extends to the control of tissues removed from his or her body. 10


Ethical Analysis

Among the various definitions of privacy, one broad definition captures its central element: privacy is "a state or condition of limited access to a person." 11 People have privacy if others lack or do not exercise access to them. They have privacy if they are left alone and do not suffer unauthorized intrusion by others. Once persons undergo genetic tests, privacy includes the right to make an informed, independent decision about whether&mdashand which&mdashothers may know details of their genome (e.g., insurers, employers, educational institutions, spouses and other family members, researchers, and social agencies).

Various justifications have been offered for rules of privacy. First, some philosophers argue that privacy rights are merely shorthand expressions for a cluster of personal and property rights, each of which can be explicated without any reference to the concept of privacy. In making this argument, Judith Jarvis Thomson holds that privacy rights simply reflect personal and property rights, such as the rights not to be looked at, not to be overheard, and not to be caused distress. 12

A second justification holds that rights to privacy are important instruments or means to other goods, including intimate relations such as trust and friendship. Being able to control access to themselves enables people to have various kinds of relationships with different people, rather than being equally accessible to all others.

A third approach finds the basis for rights to privacy in respect for personal autonomy. Decisional privacy is often very close to personal autonomy. The language of personal autonomy reflects the idea of a domain or territory of self-rule, and thus overlaps with zones of decisional privacy.

Whatever their rationale or justification, rights of privacy are the subject of ongoing debate about their scope and weight. However, their scope is not unlimited, and they do not always override all other competing interests, such as the interests of others.

Legal Issues

In the legal sphere, the principle of privacy is an umbrella concept encompassing issues of both autonomy and confidentiality. The right to make choices about one's health care is protected, in part, by the right to privacy guaranteed by the U.S. Constitution, as well as state constitutions. This includes a right to make certain reproductive choices, 13 such as whether to use genetic testing. l4 It also includes a right to refuse treatment.

An entirely different standard of privacy protects personal information. A few court decisions find protection for such information under the constitutional doctrine of privacy, 15 but more commonly, privacy protection against disclosure of personal information is found under common law tort principles. 16 In addition, there is a federal privacy act, 17 as well as state statutes protecting privacy.


Ethical Analysis

Confidentiality as a principle implies that some body of information is sensitive, and hence, access to it must be controlled and limited to parties authorized to have such access. The information provided within the relationship is given in confidence, with the expectation that it will not be disclosed to others or will be disclosed to others only within limits. The state or condition of nondisclosure or limited disclosure may be protected by moral, social, or legal principles and rules, which can be expressed in terms of rights or obligations.

In health care and various other relationships, we grant others access to our bodies. They may touch, observe, listen, palpate, and even physically invade. They may examine our bodies as a whole or in parts and parts, such as tissue, may be removed for further study, as in some forms of testing. Privacy is necessarily diminished when others have such access to us rules of confidentiality authorize us to control and thus to limit further access to the information generated in that relationship. For example, rules of confidentiality may prohibit a physician from disclosing some information to an insurance company or an employer without the patient's authorization.

Rules of confidentiality appear in virtually every code or set of regulations for health care relationships. Their presence is not surprising, because such rules are often justified on the basis of their instrumental value: if prospective patients cannot count on health care professionals to maintain confidentiality, they will be

reluctant to allow professionals the full and complete access necessary for diagnosis and treatment. Hence, rules of confidentiality are indispensable for patient and social welfare without those rules, people who need medical, psychiatric, or other treatment will refrain from seeking or fully participating in it. Another justification for rules of confidentiality is based on the principles of respect for autonomy and privacy, above. Respecting persons involves respecting their zone of privacy and accepting their decisions to control access to information about them. When people grant health care professionals access to them, they should retain the right to determine who else has access to the information generated in that relationship. Hence, the arguments for respect for autonomy and privacy support rules of confidentiality. Finally, duties of confidentiality often derive from explicit or implicit promises in the relationship. For instance, if the professional's public oath or the profession's code of ethics promises confidentiality of information, and the particular professional does not specifically disavow it, then the patient has a right to expect that information generated in the relationship will be treated as confidential. 18

There are at least two distinct types of infringements of rules of confidentiality. On the one hand, rules of confidentiality are sometimes infringed through deliberate breaches. On the other hand, rules of confidentiality are often infringed through carelessness, for example, when health care professionals do not take adequate precautions to protect the confidential information. Some commentators argue that both carelessness and modern practices of health care have rendered medical confidentiality a "decrepit concept," since it is compromised routinely in the provision of health care. 19

It is widely recognized that the rules of confidentiality are limited in at least two senses: (1) some information may not be protected, and (2) the rules may sometimes be overridden to protect other values. First, not all information is deemed confidential, and patients do not have a right to expect that such information will be protected from disclosure to others. For example, laws frequently require that health care professionals report gunshot wounds, venereal diseases, and other communicable diseases such as tuberculosis. Second, health care professionals may also have a moral or legal right (and sometimes even an obligation) to infringe rules of confidentiality, for example, to prevent a serious harm from occurring. In such cases, rules of confidentiality protect the information, but they can be overridden in order to protect some other value. Judgments about such cases depend on the probability of serious harm occurring unless confidentiality is breached. Any justified infringements of rules of confidentiality should satisfy the conditions identified earlier in the discussion of justified infringements of the principle of respect for autonomy.

Legal Issues

The legal concept of confidentiality focuses on the information that people

provide to their physicians. The protection of confidentiality is thought to serve an important public health goal in encouraging people to seek access to health care. It is thought that the patient's interest can be served only in an atmosphere of total frankness and candor. 20 Without the promise of confidentiality, people might avoid seeking medical treatment, thus potentially harming themselves as well as the community. In fact, the first doctor-patient confidentiality statute was passed in 1828 in New York during the smallpox epidemic to encourage people to seek health care. Various legal decisions have protected confidentiality of health care information, 21 as have certain state and federal statutes.

Confidentiality of health care information is also protected because disclosure of a person's medical condition can cause harm to him or her. An alternative set of legal principles-those penalizing discrimination (see below)-protects people against unfair uses of certain information.


Ethical Analysis

Issues of justice, fairness, and equity crop up in several actions, practices, and policies relating to genetic testing. It is now commonplace to distinguish formal justice from substantive justice. Formal justice requires treating similar cases in a similar way. Standards of substantive or material justice establish the identity of the relevant similarities and differences and the appropriate responses to those similarities and differences. For instance, a society has to determine whether to distribute a scarce resource such as health care according to persons' differences in need, social worth, or ability to pay.

One crucial question is whether genetic disorders or predispositions provide a basis for blocking access to certain social goods, such as employment or health insurance. Most conceptions of justice dictate that employment be based on the ability to perform particular tasks effectively and safely. For these conceptions, it is unjust to deny employment to someone who meets the relevant qualifications but also has a genetic disease. Frequently these questions of employment overlap with questions of health insurance. Practices of medical underwriting in health insurance reflect what is often called "actuarial fairness"-that is, grouping those with similar risks together so insurers can accurately predict costs, and set fair and sufficient premium rates. Although actuarial fairness may be intuitively appealing, critics argue that it does not express moral or social fairness. According to Norman Daniels, there is "a clear mismatch between standard underwriting practices and the social function of health insurance" in providing individuals with resources for access to health care 22 (see Chapter 7).

The fundamental argument for excluding genetic discrimination in health insurance amounts to an argument for establishing a right to health care. One of the central issues in debates about the distribution of health care is one's view of the

"natural lottery," in particular, a "genetic lottery." 23 The metaphor of a lottery suggests that health needs result largely from an impersonal natural lottery and are thus undeserved. But even if health needs are largely undeserved because of the role of chance, society's response to those needs may vary, as H. Tristram Engelhardt notes, depending on whether it views those needs as unfair or as unfortunate. 24 If health needs are unfortunate, but not unfair, they may be the object of individual or social compassion. Other individuals, voluntary associations, and even society may be motivated by compassion to try to meet those needs. If, however, the needs are viewed as unfair as well as unfortunate, society may have a duty of justice to try to meet those needs.

One prominent argument for the societal provision of a decent minimum of health care is that, generally, health needs are randomly distributed and unpredictable, as well as overwhelming when health crises occur. 25 Because of these features of health needs, many argue that it is inappropriate to distribute health care according to merit, societal contribution, or even ability to pay. Another version of the argument from fairness holds that health needs represent departures from normal species functioning and deprive people of fair equality of opportunity. Thus, fairness requires the provision of health care to "maintain, restore, or compensate for the loss of normal functioning" in order to ensure fair equality of opportunity. 26

Several committee members expressed concerns that these stated arguments are somewhat weakened by the fact that a number of diseases are not the result of random events, but are brought on or exacerbated by dispensable habits such as cigarette smoking and excessive alcohol ingestion. While our and other societies attempt to discourage such habits by education and taxation, there is general agreement that access to full health care must be ensured once illness develops. If a tendency to abuse alcohol, for example, were to have a genetic predisposition, an additional argument could be made for providing the same level of health care to everyone since a person does not choose his or her genetic propensities.

The argument that society should guarantee or provide a decent minimum of health care for all citizens and residents points toward a direction for health policy, but it does not determine exactly how much health care the society should provide relative to other goods it also seeks. And, within the health care budget, there will be difficult allocation questions, including how much should be used for particular illnesses and for particular treatments for those illnesses. Questions of allocation cannot be resolved in the abstract. In democratic societies, they should be resolved through political processes that express the public's will. In specifying and implementing a conception of a decent minimum, an adequate level, or a fair share of health care in the context of scarce resources, as the President's Commission noted in 1983, it is reasonable for a society to turn to fair, democratic political procedures to choose among alternative conceptions of adequate health care, and in view of "the great imprecision in the notion of adequate health care . it is especially important that the procedures used to define that level be&mdashand be perceived to be&mdashfair." 27

Legal Issues

The concept of equity serves as the underpinning for a variety of legal doctrines and statutes. Certain needy people are provided health care, including some genetics services, under government programs such as Medicaid (see Chapter 7). In addition, some legislative efforts have been made to prohibit discrimination based on genotype. For example, some states have statutes prohibiting discrimination in employment based on one's genotype. 28 And nearly all people over age 65 are deemed to have a right to care (under Medicare).


The development of genetic testing has raised numerous concerns about autonomy, confidentiality, privacy, and equity that are exacerbated by the range of contexts in which such tests are undertaken, the sheer volume of tests that could be offered, the many uses that can be made of test results, and the variety of institutions that store genetic information. To date, most genetic testing has been done in the reproductive context or with newborns, to identify serious disorders that currently or soon will affect the fetus or infant. However, the types of genetic conditions or predispositions that can potentially be tested for are much broader than those signaling serious, imminent diseases. These include characteristics (such as sex or height) that are not diseases, potential susceptibility to diseases if the person comes into contact with particular environmental stimuli, and indications that a currently asymptomatic person will suffer later in life from a debilitating disease such as Huntington disease. The genetic anomalies that can be tested for range widely in their manifestations, their severity, their treatability, and their social significance. People's ability to define themselves, to manage their destiny and self-concept, will depend in large measure on the control they have over whether they and others come to know their genetic characteristics.

Most medical testing is done within a physician-patient relationship. With genetic testing, however, the potential range of contexts in which it can be undertaken is large. Already, in the public health context, more than 4 million newborns are tested annually for metabolic disorders so that effective treatment can be started in a few hundred. Researchers are inviting people to participate in family studies and undergo genetic testing, including collection of DNA samples for present or future analyses. There are a growing number of nonmedical applications of genetic testing as well. In the law enforcement context, DNA testing is undertaken to attempt to identify criminal offenders. At least 17 states have DNA fingerprint programs for felons. 29 The armed services are collecting DNA samples from all members of the military, the primary purpose of which is to identify bodies of deceased soldiers. Employers and insurers may require people to undergo testing for genetic disorders for exclusionary purposes. One challenge for policy posed by this wide array of testing settings is that many of the existing legal

precedents about autonomy, confidentiality, and privacy apply only to the traditional doctor-patient relationship. For example, some state statutes governing confidentiality deal only with information provided to physicians and might not cover information provided to Ph.D. researchers or employers.

There seems to be great variation among institutions and among providers in the amount of attention paid to autonomy, confidentiality, and privacy. For example, some obstetricians recognize the patient's autonomy by providing them the information about maternal serum alpha-fetoprotein (MSAFP) screening but acknowledging the patient's right to decide whether or not to undergo the test. Other obstetricians run the test on blood gathered from the woman for other purposes, so the woman does not even know she has been the subject of the test unless the obstetrician delivers the bad news that she has had an abnormal result.

Geneticists differ with respect to the emphasis they place on the confidentiality of the results of genetic testing. In a survey by Dorothy Wertz and John Fletcher, 30 numerous geneticists suggested that there were at least four situations in which they would breach confidentiality and disclose genetic information without the patient's permission, even over the patient's refusal: (1) 54 percent said they would disclose to a relative the risk of Huntington disease (2) 53 percent said they would disclose the risk of hemophilia A (3) 24 percent said they would disclose genetic information to a patient's employer and (4) 12 percent said they would disclose such information to the patient's insurer. Primary care physicians may be even more likely to disclose such information. 31 Health care providers should explain their policies for disclosure in advance, including for disclosure to relatives.

Institutions that store DNA samples 32 or store the results of genetic tests also differ in the amount of respect they give to autonomy, confidentiality, and privacy. 33 Some institutions do additional tests on DNA samples without the permission of the person who provided the sample. Some share samples with other institutions. Some store samples or information with identifiers attached, rather than anonymously. Indeed, storage conditions themselves differ widely. Some newborn screening programs store filter papers in a temperature-controlled, secure setting others merely pile them in a file cabinet or storage closet. Programs also differ in the length of time the sample or the test results are maintained.

Once DNA material has been submitted, there are few safeguards concerning other present or future uses that may be made of the material. DNA from the blood spots collected for newborn screening can now be extracted for further testing. 34 No standards or safeguards currently exist to govern the appropriate use of DNA analysis and storage from newborn screening tests. These possibilities raise questions about the need to obtain consent for additional and subsequent uses (particularly since consent is almost never obtained initially in newborn screening), as well as questions about the duty to warn if disorders are detected in the blood by using the new DNA extraction testing techniques.

The issue of confidentiality of genetic information will be underscored with

the introduction of ''optical memory cards," a credit card-sized device that stores medical information. 35 These cards have already been introduced for use in Houston city health clinics. There is sufficient computer memory on the cards to include genetic information about the person and, in the future, to include a person's entire genome.

Congressional legislation has been introduced that would require all patients to use optical memory cards. This bill, the Medical and Health Insurance Information Reform Act of 1992, would mandate a totally electronic system of communication between health care providers and insurers. Such a system would be based either on the optical memory card (with a microchip capable of storing data) or on a card similar to an Automated Teller Card (which simply provides access to data stored elsewhere).


The principles of autonomy, privacy, confidentiality, and equity place great weight on individuals' rights to make personal decisions without interference. This is due, in part, to the importance placed on individuals in our culture and our legal system. However, individual rights are not without bound, and the area of genetics raises important questions of where individual rights end and where responsibilities to a group&mdashsuch as one's family or the larger society&mdashbegin.

Medicine is generally practiced within this culture of individual rights (with provisions for patients' right to refuse treatment and right to control the dissemination of medical information about themselves), but there have been circumstances in which the medical model has been supplanted by the public health model, which encourages the prevention of disease&mdashfor example, by requiring that certain medical intervention (such as vaccinations) be undertaken and by warning individuals of health risks (e.g., through educational campaigns against smoking or through contact tracing with respect to venereal diseases). Some commentators have suggested that the public health model be applied to genetics, 36 with mandatory genetic screening and even mandatory abortion of seriously affected fetuses. A related measure might be warning people of their risk of genetic disorders.

There are several difficulties with applying the public health model to genetics, however. Certain infectious diseases potentially put society as a whole at immediate risk since the diseases can be transmitted to a large number of people in a short time. The potential victims are existing human beings who may be total strangers to the affected individual. In contrast to infectious disease, the transmission of genetic diseases does not present an immediate threat to society. Whereas infectious disease can cause rapid devastation to a community, the transmission of genetic disorders to offspring does not necessarily have an immediate detrimental effect, but rather creates a potential risk for a future generation in society. 37 U.S.

Supreme Court cases dealing with fundamental rights have held that harm in the future is not as compelling a state interest as immediate harm. 38

Moreover, the very concept of "prevention" does not readily fit most genetic diseases. In the case of newborn screening for PKU, treatment can prevent mental retardation. However, with many genetic diseases today, the genetic disease itself is not being prevented, but rather the birth of a particular individual with the disease is prevented (e.g., when a couple, each of whom is heterozygous for a serious recessive disorder, chooses not to conceive or chooses to terminate the pregnancy of a fetus who is homozygous for the disorder). This sort of prevention cannot be viewed in the same way as preventing measles or syphilis, for example. There is a great variation among people in their view of disability and what constitutes a disorder to be "prevented." Many people will welcome a child with Down syndrome or cystic fibrosis into their family. In addition, some individuals have religious or other personal moral objections to abortion even mandatory carrier status screening or prenatal screening without mandatory abortion may be objected to because people who object to abortion are concerned that the abortion rate will rise among those in the general population who learn of genetic risks to their fetus. Furthermore, some people with a particular disability or genetic risk may view mandatory genetic testing for that risk or disability as an attempt to eradicate their kind, as a disavowal of their worth.

Mandatory genetic testing might also have devastating effects on the individuals who are tested. Unlike infectious disease (which can be viewed as external to the person), genetic disease may be viewed by people as an intractable part of their nature. Persons who learn, against their will, that they carry a defective gene may view themselves as defective. This harm is compounded if they did not choose to learn the information voluntarily. This assault on personal identity is less likely with infectious diseases, although AIDS and genital herpes (for example) can also have a negative impact on self-image. Moreover, most genetic defects, unlike most infectious diseases, generally cannot now be corrected. 39 Thus, the unasked-for revelation that occurs through mandatory genetic testing can haunt the person throughout his or her life and can have widespread reverberations in the family, including others who may be at risk or related as partners. The information can serve as the basis for discrimination against the individual.

Additionally, policy concerns raised by attempts to stop the transmission of genetic diseases differ from those addressed to infectious diseases because genetic diseases may differentially affect people of different races or ethnic backgrounds. For that reason, some commentators contest the applicability of the infectious disease model to government actions regarding genetic disorders. Catherine Damme notes that "unlike infectious disease which [generally] knows no ethnic, racial, or gender boundaries, genetic disease is the result of heredity"&mdashleaving open the possibility for discriminatory governmental actions. 40

The government has discretion with respect to which infectious diseases it tackles. For example, it can decide to require screening for syphilis but not

chlamydia, or to require vaccinations for smallpox but not for diphtheria. Government action with respect to genetic diseases is likely to be regarded much differently, especially with respect to disorders for which an effective treatment does not exist and, consequently, the only medical procedure available is the abortion of an affected fetus. Minority groups who have been discriminated against in the past may view a screening program that targets only disorders that occur within their racial or ethnic group as an additional attack, and may view abstention from reproduction or the abortion of offspring based on genetic information as a form of genocide. 41

Those commentators who argue that the infectious disease precedents justify mandatory genetic screening fail to recognize that even in the case of infectious disease, very few medical procedures are mandated for adults. Adults are not forced to seek medical diagnosis and treatment even if they have a treatable infectious disease. Laws that required compulsory infectious disease screening prior to marriage (e.g., for venereal disease) are being repealed. For example, New York abolished its requirements for premarital gonorrhea and syphilis testing. One of the reasons for the abolition of the requirements was that they were not the most appropriate way to reach the population at risk. 42

Mandating diagnosis and treatment for genetic disorders is particularly problematic when the concept of disease is so flexible. Arno Motulsky has noted that "[t]he precise definition of 'disease' regardless of etiology, is difficult." 43 He notes that maladies such as high blood pressure and mental retardation are based on arbitrary cutoff levels. David Brock similarly noted that most disorders lie between the extremes of Tay-Sachs disease and alkaptonuria what a physician advises "depends as much on the physician's ethical preconceptions as his medical experience." 44

Despite the fact that the public health model does not fit the situation of genetics, the individual rights model should not be seen as absolute. There are certain situations in which the values of autonomy, privacy, confidentiality, and equity should give way to prevent serious harm to others. Determining the exceptions to these general principles is no easy matter, however. There may be instances in which harm can be prevented by violating one of these principles, but in which the value of upholding the principles will nonetheless outweigh the chance of averting harm. In each instance, it will be necessary to assess several factors: How serious is the harm to be averted? Is violating one of the principles the best way to avert the harm? What will be the medical, psychological, and other risks of violating the principle? What will be the financial costs of violating the principle?

The following section addresses the issues raised by the application of these principles&mdashautonomy, privacy, confidentiality, and equity&mdashin the contexts of clinical genetics, other medical practices, genetics research, and so forth. It also provides guidance for determining the appropriate circumstances for exceptions to these principles. The chapter concludes with the committee's recommendations on these issues.



One important way to ensure autonomy with respect to genetic testing is to provide adequate information upon which a person can make a decision whether or not to undergo testing. A proper informed consent in medicine generally involves the presentation of information about the risks, benefits, efficacy, and alternatives to the procedure being undertaken. In addition, recent cases and statutes have recognized the importance of disclosures of any potential conflicts of interest that the health care professional recommending the test may have, such as a financial interest in the facility to which the patient is being referred. In the genetics context, this would include disclosure about equity holdings or ownership of the laboratory, dependence on test reimbursement to cover the costs of counseling, patents, and so forth. It would also include disclosure of any planned subsequent uses of the tissue samples, even if such uses are to be anonymous.

Various kinds of information are relevant to people who are attempting to exercise their autonomy by deciding whether or not to undergo genetic testing. This includes information about the severity, potential variability, and treatability of the disorder being tested for. If, for example, carrier status testing is being proposed for a pregnant woman or prenatal testing is being proposed for her fetus, she should be told whether the disorder at issue can be prevented or treated, or whether she will be faced with a decision about whether or not to abort (see Chapters 2, 4, and 5). The proposed informed consent guidelines for research involving genetic testing suggested by the Alliance of Genetic Support Groups provide an excellent starting point for the development of informed consent policies in the genetics area (see Chapter 4).

The potential development of multiplex testing adds another wrinkle to the issue of informed consent for genetic testing. If 100 disorders are tested from the same blood sample, it may be difficult to apply the current model of informed consent in which a health care provider gives information about each disorder and the efficacy of each test to the patient in advance of the testing. The difficulty in applying the traditional mechanisms for achieving informed consent does not provide an excuse for failing to respect a patient's autonomy and need for information, however. New mechanisms may have to be developed to protect these rights. It will be possible to have results reported back to the physician and patient only about those tests (or types of tests) the patient chooses. The choices can be made by the patient, based, for example, on the patient learning through a computer program about the various disorders and the various tests. Or the choices can be made according to general categories&mdashfor example, the patient might choose to have multiplex testing but choose not be informed of the results of testing for untreatable or unpreventable disorders 45 (see Chapters 1, 3, and 4).

In addition to the recognition that people are entitled to information before

they make decisions, a second application of the autonomy principle comes with the recognition that the decision to participate in genetic testing and other genetics services must be voluntary. Voluntariness has been a recognized principle in past recommendations and practices involving genetics. This is in keeping with the recognized right of competent adults to refuse medical intervention, as well as the right to refuse even the presentation of medical information in the informed consent context. 46 If, for example, it becomes possible to accurately screen fetal cells isolated from a pregnant woman's blood in order to determine the genetic status of the fetus, state public health departments might be interested in requiring the test on the grounds that it is a minimally invasive procedure that can provide information to the woman (perhaps leading her to abort an affected fetus and saving the state money for care of that infant). Mandating such a test, however, would show insufficient respect for the woman's autonomy and would violate her right to make reproductive decisions.

Special Issues in the Screening and Testing of Children

The expansion of available tests fostered by the Human Genome Project will present complicated issues with respect to the testing of newborns and other children. Although there are clear legal precedents stating that adults are free to refuse even potentially beneficial testing and treatment, legal precedents provide that children can be treated without their consent (and over their parents' refusal) to prevent serious imminent harm. The U.S. Supreme Court has said that, while parents are free to make martyrs of themselves, they are not free to make martyrs of their children. 47 Medical intervention over parents' objection has been allowed in situations in which a child's life was in imminent danger and the treatment posed little risk of danger in itself. 48 Blood transfusions have been ordered for the children of Jehovah's Witnesses when the child's life was imminently endangered. 49

All states have programs to screen newborns for certain inborn errors of metabolism for which early intervention with treatment provides a clear medical benefit to the child, such as phenylketonuria. Currently, the statutes of at least two jurisdictions (the District of Columbia and Maryland) clearly provide that newborn screening is voluntary. 50 In at least two states (Montana and West Virginia), screening is mandatory and there is no legal provision for parental objection or refusal based on religious grounds. 51 In the rest of the states, there are grounds for parental refusal for religious or other reasons. However, although the majority of states allow objection to screening on some grounds, very few statutes require that the parents or guardians of an infant either be sufficiently informed that they can choose whether or not their infant should submit to the screening or be told they have the right to object. Two states (Missouri and South Carolina) have criminal penalties for parents who refuse newborn screening of their children. 52

The idea behind mandatory newborn screening is a benevolent one&mdashto try to ensure that all children get the benefits of screening for PKU and hypothyroidism,

for which early treatment can make a dramatic difference in the child's well-being by preventing mental retardation. Yet there is little evidence that it is necessary to make a newborn screening program mandatory to ensure that children are screened under the program. Recent studies show that the few states with voluntary newborn screening programs screen a higher percentage of newborns than some states with mandatory newborn screening programs for 1990, voluntary programs reported reaching 100 percent of newborns in their states, while some states with mandatory programs report reaching 98 percent, and some even less than 96 percent. 53 Relevant research has suggested that even when a newborn screening program is completely voluntary and parents may refuse for any reason, the actual refusal rate is quite low, about 0.05 percent (27 of 50,000 mothers). In that study, most nurses reported that it required only one to five minutes to inform a mother about newborn screening. 54

Newborn screening for PKU&mdashlike a necessary blood transfusion for a child over the parents' refusal&mdashhas been justified on the basis of the legal doctrine of parens patriae, where the state steps in to order an intervention to protect a child from substantial, imminent harm. In the era of the Human Genome Project, when additional tests are being developed, some people are promoting newborn screening in part for less immediate and less clear benefits. Proposed guidelines have suggested that another benefit of newborn screening "might take the form of inscription in registries for later reproductive counseling (material PKU) or of surveillance of phenotypes (congenital adrenal hyperplasia)." 55 To achieve such an outcome, the resulting children would need to be followed until the age when reproductive counseling was appropriate&mdashor when symptoms manifest&mdasha daunting task in this age of mobility.

The first newborn screening programs were for disorders in which early treatment of the newborn was effective. Increasingly, however, testing is suggested for untreatable disorders. In such instances, the justification is not the benefit to the newborn but the benefit to the parents for future reproductive plans. For such reasons, several countries&mdashand some states in the United States (e.g., Pennsylvania)&mdashscreen newborns for Duchenne muscular dystrophy. This medical intervention has no immediate medical benefit for the newborn, and carrier screening of the parents could be obtained through other methods, even when (as in the case of Duchenne muscular dystrophy and some other conditions) they may not realize they are at risk.

Moreover, screening newborns for genes for untreatable disorders or carrier status may have disadvantages. The children may be provided with information that, at the age of consent, they would rather not have. Parents might treat them differently if the results are positive. Parents may stigmatize or reject children with the abnormal genes, or may be less willing to devote financial resources to education or other benefits for such children. In addition, release of the test results might cause them to be uninsurable, unemployable, and unmarriageable.

There are additional benefits from voluntariness in newborn screening. In-

forming parents about newborn screening in advance of testing allows quality assurance: parents can check to see if the sample was actually drawn. As children are being released from the hospital increasingly early, due to insurance pressures, they might receive a false negative result because blood levels of phenylalanine have not yet risen sufficiently to be detected if elevated. Informed motivated parents may need to bring their babies to be screened after release from the hospital in order to ensure an accurate test result. The recommended informed consent process can provide the necessary education and motivation that will be required to make the return trip far better than mandatory programs.

In the postgenome era, people will be facing the possibility of undergoing many more genetic tests in their lifetimes, and will need to master a wealth of genetic information that is relevant to their health, their reproductive plans, and the choices they make about what to eat, where to live, and what jobs to take. The more settings in which they can be informed about genetics, the more able they will be to make these decisions. In addition, when newborn screening programs are voluntary, there is a greater chance that parents will be provided with material in advance about the disorder and have their questions answered, thus presenting the possibility that they will view it more seriously and will make a greater effort to ensure that the child receives proper treatment if a condition is detected. The disclosure of information to parents about newborn screening prior to newborn screening can be an important tool for public education about genetics.

Mandatory newborn screening should only be undertaken if there is strong evidence of benefit to the newborn from effective treatment at the earliest possible age (e.g., PKU and congenital hypothyroidism). Under this principle, screening for Duchenne muscular dystrophy would not be justified. In addition, mandatory newborn screening for cystic fibrosis would currently not be justified. 56 A prospective double-blind study in Wisconsin (the only controlled study on the subject) has not found benefits of early detection in newborn screening for CF the treatment of children could be initiated with just as successful results based on the occurrence of symptoms. In addition to its lack of clear benefit, newborn screening for CF has a clear downside. Screening by its nature is overly broad in newborn screening for cystic fibrosis, for example, "only 6.1 percent of infants with positive first tests [in the Colorado and Wyoming program] were ultimately found to have cystic fibrosis on sweat chloride testing." 57 Yet one-fifth of parents with false positives on newborn screening for cystic fibrosis "had lingering anxiety about their children's health." 58 Of the parents whose infants had initial, later disproven positive reports of CF in the Wisconsin study, 5 percent still believed a year later that their child might have CF. 59 Such a reaction may influence how parents relate to their child. A report on the Wisconsin newborn screening for CF stated that of the 104 families with false positives, 8 percent planned to change their reproductive plans and an additional 22 percent were not sure whether they would change their reproductive plans. 60 In fact, in France, the newborn screen-

ing program for cystic fibrosis was terminated at the request of parents who objected to the high number of false positives. 61 Denmark stopped screening for alpha-1-antitrypsin deficiency because of negative long-term effects on the mother-child interactions associated with identifying the infant's alpha-l-antitrypsin deficiency. 62

Even in cases where a treatment is available for a disorder detectable through newborn screening, it may not be of unequivocal benefit if started after symptoms appear. Treatment of children identified through screening for maple syrup urine disease may have only limited effectiveness at best, and parents may face a quandary about whether or not to treat. Even if hypothetical benefits exist, newborn screening programs need close scrutiny to determine if the necessary treatments are actually provided to the children. In states that support screening but not treatment, families may be unable to afford treatment and thus children may not benefit from screening. Many children with sickle cell anemia, for example, do not get their necessary penicillin prophylaxis. 63 Although most states provide education about diet and nutrition to parents of infants with PKU, not all states provide the expensive essential diet or other food assistance.

Beyond the issue of the testing of newborns in state-sponsored programs, there are more general issues regarding the genetic testing of children in clinical settings. Some technologies designed to identify affected individuals will also provide information about carrier status. If an infant is tested for sickle cell anemia, for example, the test will reveal whether the infant is a carrier. In that case, the carrier status information is a by-product of the test for sickle cell anemia since obtaining information on carrier status is not the primary purpose of the testing. Questions arise as to whether that information should be reported to the infant's parents.

One advantage to reporting the information is that it is relevant to the parents' future reproductive plans. If the infant is a carrier, at least one of the parents is a carrier. If both are carriers, then they are at 25 percent risk of having an affected child. On the other hand, there are disadvantages to the reporting of such information to parents. Unless education and counseling are available, they may erroneously worry that the child will be affected with a disease related to the carrier status. They may stigmatize the child or otherwise treat the child as different. In addition, the disclosure of the child's carrier status may result in disruption to the family if neither of the social parents is a carrier (which most often indicates that another man fathered the child).

Since numerous tests can be added in a newborn screening program using the initial filter paper spot, the pressure to add new tests may be difficult to resist. Under the American Society of Human Genetics (ASHG) guidelines, however, before tests are added, a rigorous analysis should be made about who will benefit, who will be harmed, and who consents. In state programs for newborn screening, subsequent anonymous uses of samples for research may be undertaken.

Voluntariness of Subsequent Uses

Many state newborn screening programs, as well as research and clinical facilities, store the filter paper spots or other DNA samples for long periods after their initial use in genetic testing. Some states use newborn screening spots to experiment with new tests, and this would seem permissible as long as the samples are not identified and the uses were not anticipated prior to the initial test. 64 If the samples are identified, the person's permission would be required. However, researchers constitute just one group that might want access to the newborn screening spots. Such spots are of interest to law enforcement officials in one case, police contacted a newborn screening laboratory when they were trying to identify a young murder victim.

The American Society of Human Genetics issued a statement on DNA banking and DNA data banking in 1990. 65 ASHG recommended the purposes for which samples are acquired for DNA analysis be defined in advance:

Later access to DNA samples or to the profiles for other purposes should be permitted only when (a) a court orders the information to be released, (b) the data are to be anonymously studied, or (c) the individual from whom the sample was obtained provides written permission. In general, regardless of the purpose for which it was compiled, this information should be accorded at least the confidentiality that is accorded to medical records. 66


Confidentiality is meant to encourage the free flow of information between patient and physician so that the patient's sickness may be adequately treated. The protection of confidentiality is also justified as a public health matter, since ill people may not seek medical services in the first place if confidentiality is not protected. As a legal matter, confidentiality is generally protected in the doctor-patient relationship. However, genetic testing may not always occur within a doctor-patient relationship: a non-M.D. scientist may undertake the testing, or screening may occur in the employment setting. Moreover, it is not just the result of the test that raises concern about confidentiality. The sample itself may be stored (as in DNA banking or family linkage studies) for future use.

Genetic information is unlike other medical information. It reveals not only potential disease or other risks to the patient, but also information about potential risks to the person's children and blood relatives. The fact that geneticists may wish to protect third parties from harm by breaching confidentiality and disclosing risks to relatives is evidenced in the study by Wertz and Fletcher, cited earlier, in which half of the geneticists surveyed would disclose information to relatives over a patient's refusal. The geneticist's desire to disclose is based on the idea that the information will help the relative avoid harm. Yet this study indicated that about the same number of geneticists would disclose to the relative when the

Personality Inventories

Many personality inventories used in career planning are based on Psychiatrist Carl Jung's personality theory. He believed four pairs of opposite preferences—the way individuals choose to do things— make up people's personalities. They are extroversion and introversion (how one energizes), sensing and intuition (how one perceives information), thinking or feeling (how one makes decisions), and judging and perceiving (how one lives his or her life). One preference from each pair makes up an individual's personality type.

Career counselors often use results from assessments based on Jungian Personality Theory, such as the Myers-Briggs Type Indicator (MBTI), to help clients choose careers. They believe individuals with a particular personality type are better suited to specific occupations. An example would be that an introvert would not do well in a career that requires him or her to be around other people all the time.

Author information


deCODE genetics/Amgen, Inc., Reykjavik, Iceland

Rosa B. Thorolfsdottir, Gardar Sveinbjornsson, Patrick Sulem, Stefan Jonsson, Gisli H. Halldorsson, Pall Melsted, Erna V. Ivarsdottir, Olafur B. Davidsson, Ragnar P. Kristjansson, Gudmar Thorleifsson, Anna Helgadottir, Solveig Gretarsdottir, Gudmundur Norddahl, Sridharan Rajamani, Vinicius Tragante, Bjarni V. Halldorsson, Ingileif Jonsdottir, David O. Arnar, Unnur Thorsteinsdottir, Daniel F. Gudbjartsson, Hilma Holm & Kari Stefansson

Faculty of Medicine, University of Iceland, Reykjavik, Iceland

Rosa B. Thorolfsdottir, Bjarni Torfason, Ingileif Jonsdottir, David O. Arnar, Unnur Thorsteinsdottir & Kari Stefansson

Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI, USA

Jonas B. Nielsen & Cristen J. Willer

Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA

Jonas B. Nielsen & Cristen J. Willer

School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

Pall Melsted & Daniel F. Gudbjartsson

Department of Cardiothoracic Surgery, Landspitali University Hospital, Reykjavik, Iceland

Bjarni Torfason & Atli S. Valgardsson

Department of Medicine, Akureyri Regional Hospital, Akureyri, Iceland

Department of Cardiology, Division Heart & Lungs, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands

Vinicius Tragante & Folkert W. Asselbergs

HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology, Levanger, Norway

Oddgeir L. Holmen & Kristian Hveem

K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, Norwegian University of Science and Technology, Trondheim, Norway

Oddgeir L. Holmen & Kristian Hveem

Department of Cardiology, St. Olav’s University Hospital, Trondheim, Norway

Durrer Center for Cardiovascular Research, Netherlands Heart Institute, Utrecht, The Netherlands

Institute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, UK

Farr Institute of Health Informatics Research and Institute of Health Informatics, University College London, London, UK

Departments of Medicine, Pharmacology, and Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA

Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

Center For Preventive Medicine, Oslo University Hospital and Medical Faculty, University of Oslo, Oslo, Norway

TIMI Study Group, Division of Cardiovascular Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA

Department of Community Medicine, UiT The Arctic University of Norway, Tromsø, Norway

Reykjavik University, Reykjavik, Iceland

Department of immunology, Landspitali University Hospital, Reykjavik, Iceland

Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Levanger, Norway

Department of Medicine, Landspitali University Hospital, Reykjavik, Iceland

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Pros and cons of genetic diagnostic tests

Greiner said that some of her patients ask her why they should do prenatal genetic testing because if a positive result is found, the genetic problem detected in the baby can't be changed, fixed or treated.

She responds to this question by telling her patients that no one likes a surprise. Knowing positive test results in advance can help expectant parents plan and prepare themselves as well as their home for a baby who may have special needs.

Greiner said women need to ask themselves whether a positive diagnostic test result would cause them anxiety if they choose to continue the pregnancy, or if these genetic findings may provide reassurance if they decide to terminate the pregnancy as a result of the diagnosis.

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