Thompson & Thompson Genetics in Medicine, 8th Edition

CHAPTER 16. Risk Assessment and Genetic Counseling

In this chapter, we present the fundamentals of the practice of genetic counseling as applied to families in which an individual is known or suspected to have a hereditary condition. Genetic counseling includes a discussion of the natural history of the disease as well as determination of the risk for disease in other family members based on the inheritance pattern, empirical risk figures, and medical testing, especially molecular genetic and genomic testing. Counseling includes a discussion of approaches available to mitigate or reduce the risk for heritable disease. Finally, the counselor carries out a careful assessment of the psychological and social impact of the diagnosis on the patient and family and works to help the family cope with the presence of a heritable condition.

Family History in Risk Assessment

Family history is clearly of great importance in diagnosis and risk assessment. Applying the known rules of mendelian inheritance, as introduced in Chapter 7, allows the geneticist to provide accurate evaluations of risk for disease in relatives of affected individuals. Family history is also important when a geneticist assesses the risk for complex disorders, as discussed in Chapter 8 and elsewhere in this book. Because a person's genes are shared with his or her relatives, family history provides the clinician with information on the impact that an individual's genetic makeup might have on one's health, using the medical history of relatives as an indicator of one's own genetic susceptibilities. Furthermore, family members often share environmental factors, such as diet and behavior, and thus relatives provide information about both shared genes and shared environmental factors that may interact to cause the common, genetically complex diseases. Having a first-degree relative with a common disease of adulthood—such as cardiovascular disease, cancer of the breast, cancer of the colon or prostate, type 2 diabetes, osteoporosis, or asthma—raises an individual's risk for the disease approximately twofold to threefold relative to the general population, a moderate increase compared with the average population risk (see Box). As discussed in Chapter 8, the more first-degree relatives one has with a complex trait and the earlier in life the disease occurs in a family member, the greater the load of susceptibility genes and environmental exposures likely to be present in the patient's family. Thus consideration of family history can lead to the designation of a patient as being at high risk for a particular disease on the basis of family history. For example, a male with three male first-degree relatives with prostate cancer has an 11-fold greater relative risk for development of the disease than does a man with no such family history.

Family History in Risk Assessment

High Risk

• Age at onset of a disease in a first-degree relative relatively early compared to the general population

• Two affected first-degree relatives

• One first-degree relative with late or unknown disease onset and an affected second-degree relative with premature disease from the same lineage

• Two second-degree maternal or paternal relatives with at least one having premature onset of disease

• Three or more affected maternal or paternal relatives

• Presence of a “moderate-risk” family history on both sides of the pedigree

Moderate Risk

• One first-degree relative with late or unknown onset of disease

• Two second-degree relatives from the same lineage with late or unknown disease onset

Average Risk

• No affected relatives

• Only one affected second-degree relative from one or both sides of the pedigree

• No known family history

• Adopted person with unknown family history

From Scheuner MT, Wang SJ, Raffel LJ, et al: Family history: a comprehensive genetic risk assessment method for the chronic conditions of adulthood, Am J Med Genet 71:315-324, 1997; quoted in Yoon PW, Scheuner MT, Peterson-Oehlke KL, et al: Can family history be used as a tool for public health and preventive medicine? Genet Med 4:304-310, 2002.

Determining that an individual is at increased risk on the basis of family history can have an impact on individual medical care. For example, two individuals with deep venous thrombosis—one with a family history of unexplained deep venous thrombosis in a relative younger than 50 years and another with no family history of any coagulation disorder—should receive different management with respect to testing for factor V Leiden or prothrombin 20210G>A and anticoagulation therapy (see Chapter 8). Similarly, having a first-degree relative with colon cancer is sufficient to trigger the initiation of colon cancer screening by colonoscopy at the age of 40 years, 10 years earlier than for the general population. This is because the cumulative incidence for development of the disease for someone 40 years old with a positive family history equals the risk for someone at the age of 50 years with no family history (see Fig. 18-1). The increase in risk is even more pronounced if two or more relatives have had the disease, an empirical observation that has driven standards of clinical care for screening in this condition.

Family history is admittedly an indirect method of assessing the contribution of an individual's own genetic variants to health and disease susceptibility. Direct detection of genetic risk factors and demonstrating that they are valid for guiding health care is a major challenge in applying genomics to medicine, as we will take up in Chapter 18.

Genetic Counseling in Clinical Practice

Clinical genetics is concerned with the diagnosis and management of the medical, social, and psychological aspects of hereditary disease. As in all other areas of medicine, it is essential in clinical genetics to do the following:

• Make a correct diagnosis, which often involves laboratory testing, including genetic testing to find the mutations responsible.

• Help the affected person and family members understand and come to terms with the nature and consequences of the disorder.

• Provide appropriate treatment and management, including referrals to other specialist providers as needed.

Just as the unique feature of genetic disease is its tendency to recur within families, the unique aspect of genetic counseling is its focus on both the original patient and also on members of his or her family, both present and future. Genetic counselors have a responsibility to do the following:

• Work with the patient to inform other family members of their potential risk.

• Offer mutation or other testing to provide the most precise risk assessments possible for other family members.

• Explain what approaches are available to the patient and family members to modify these risks.

Finally, genetic counseling is not limited to the provision of information and identification of individuals at risk for disease; rather, it is a process of exploration and communication. Genetic counselors define and address the complex psychosocial issues associated with a genetic disorder in a family and provide psychologically oriented counseling to help individuals adapt and adjust to the impact and implications of the disorder in the family. For this reason, genetic counseling may be most effectively accomplished through periodic contact with the family as the medical or social issues become relevant to the lives of those involved (see Box earlier).

Genetic Counseling Providers

Clinical genetics is particularly time-consuming in comparison with other clinical fields because it requires extensive preparation and follow-up in addition to time for direct contact with patients. In many countries, genetic counseling is provided by physicians. However, in the United States, Canada, the United Kingdom, and a few other countries, genetic counseling services are often provided by genetic counselors or nurse geneticists, professionals specially trained in genetics and counseling, who serve as members of a health care team with physicians. Genetic counseling in the United States and Canada is a self-regulating health profession with its own board (the American and Canadian Boards of Genetic Counselors) for accreditation of training programs and certification of practitioners. Some states in the United States are also licensing genetic counselors. Nurses with genetics expertise are accredited through a separate credentialing commission.

Genetic counselors and nurse geneticists play an essential role in clinical genetics, participating in many aspects of the investigation and management of genetic problems. A genetic counselor is often the first point of contact that a patient has with clinical genetic services, provides genetic counseling directly to individuals, helps patients and families deal with the many psychological and social issues that arise during genetic counseling, and continues in a supportive role and as a source of information after the clinical investigation and formal counseling have been completed. Genetic counselors are also active in the field of genetic testing; they provide close liaison among the referring physicians, the diagnostic laboratories, and the families themselves. Their special expertise is invaluable to clinical laboratories because explaining and interpreting genetic testing to patients and referring physicians often requires a sophisticated knowledge of genetics and genomics, as well as excellent communication skills.

Common Indications for Genetic Counseling

Table 16-1 lists some of the most common situations that lead people to pursue genetic counseling. Individuals seeking genetic counseling (referred to as the consultands) may themselves be the probands in the family, or they may be the parents of an affected child or have relatives with a potential or known genetic condition. Genetic counseling is also an integral part of prenatal testing (see Chapter 17) and of genetic testing and screening programs (discussed in Chapter 18).

TABLE 16-1

Common Indications for Genetic Counseling


Established standards of medical care require that providers of genetic services obtain a history that includes family and ethnic information, inquire as to possible consanguinity, advise patients of the genetic risks to them and other family members, offer genetic testing or prenatal diagnosis when indicated, and outline the various treatment or management options for reducing the risk for disease. Although genetic counseling case management must be individualized for each patient's needs and situation, a generic approach can be summarized (Table 16-2). In general, patients are not told what decisions to make with regard to the various testing and management options but are instead provided with information and support in coming to a decision that seems most appropriate for the patients, the consultands, and their families. This approach to counseling, referred to as nondirective counseling, has its origins in the setting of prenatal counseling, where the guiding principle is respect for an individual couple's autonomy, that is, their right to make reproductive choices free of coercion (see Chapter 19).

TABLE 16-2

Genetic Counseling Case Management


Managing the Risk for Recurrence in Families

Many families seek genetic counseling to ascertain the risk for heritable disease in their children and to learn what options are available to reduce the risk for recurrence of the particular genetic disorder in question. Genetic laboratory tests for carrier testing (karyotyping, biochemical analysis, or genome analysis) are frequently used to determine the actual risk to couples with a family history of a genetic disorder. Genetic counseling is recommended both before and after such testing, to assist consultands in making an informed decision to undergo testing, as well as to understand and to use the information gained through testing.

When family history or laboratory testing indicate an increased risk for a hereditary condition in a future pregnancy, prenatal diagnosis, described in Chapter 17, is one approach that can often be offered to families. Prenatal diagnosis is, however, by no means a universal solution to the risk for genetic problems in offspring. There are disorders for which prenatal diagnosis is not available and, for many parents, pregnancy termination is not an acceptable option, even if prenatal diagnosis is available. Preimplantation diagnosis by blastocyst or blastomere biopsy (see Chapter 17) avoids the problems of pregnancy termination but requires in vitro fertilization.

Other measures besides prenatal diagnosis are available for the management of recurrence and include the following:

• Genetic laboratory tests for carrier testing can sometimes reassure couples with a family history of a genetic disorder that they themselves are not at increased risk for having a child with a specific genetic disease. In other cases, such tests indicate that the couple is at increased risk. Genetic counseling is recommended both before and after such testing, to assist consultands in making an informed decision to undergo testing, as well as understanding and using the information gained through testing.

• If the parents plan to have no more children or no children at all, contraception or sterilization may be their choice, and they may need information about the possible procedures or an appropriate referral.

• Adoption is a possibility for parents who want a child or more children.

• Artificial insemination may be appropriate if the father has a gene for an autosomal dominant or X-linked defect or has a heritable chromosome defect, but it is obviously not indicated if it is the mother who has such a defect. Artificial insemination is also useful if both parents are carriers of an autosomal recessive disorder. In vitro fertilization with a donated egg may be appropriate if the mother has an autosomal dominant defect or carries an X-linked disease. In either case, genetic counseling and appropriate genetic tests of the sperm or egg donor should be part of the process.

If the parents decide to terminate a pregnancy, provision of relevant information and support is an appropriate part of genetic counseling. Periodic follow-up through additional visits or by telephone is often arranged for a few months or more after a pregnancy termination.

Psychological Aspects

Patients and families dealing with a risk for a genetic disorder or coping with the illness itself are subject to varying degrees of emotional and social stress. Although this is also true of nongenetic disorders, the concern generated by knowledge that the condition might recur, the guilt or censure felt by some individuals, and the need for reproductive decisions can give rise to severe distress. Many persons have the strength to deal personally with such problems; they prefer receiving even bad news to remaining uninformed, and they make their own decisions on the basis of the most complete and accurate information they can obtain. Other persons require much more support and may need referral for psychotherapy. The psychological aspects of genetic counseling are beyond the scope of this book, but several texts cited in the General References at the end of this chapter give an introduction to this important field (see Box).

Genetic Counseling and Risk Assessment

The purpose of genetic counseling is to provide information and support to families at risk for having, or who already have, members with birth defects or genetic disorders. Genetic counseling helps the family or individual to do the following:

• Comprehend the medical facts, including the diagnosis, the probable course of the disorder, and the available management.

• Understand the way heredity contributes to the disorder and the risk for recurrence for themselves and other family members.

• Understand the options for dealing with the risk for recurrence.

• Identify those values, beliefs, goals, and relationships affected by the risk for or presence of hereditary disease.

• Choose the course of action that seems most appropriate to them in view of their risk, their family goals, and their ethical and religious standards.

• Make the best possible adjustment to the disorder or to the risk for recurrence of that disorder, or both, by providing supportive counseling to families and making referrals to appropriate specialists, social services, and family and patient support groups.

Genetic counselors often refer a patient and family with a genetic disorder or birth defect to family and patient support groups. These organizations, which can be focused either on a single disease or on a group of diseases, can help those concerned to share their experience, to learn how to deal with the day-to-day problems caused by the disorder, to hear of new developments in therapy or prevention, and to promote research into the condition. Many support groups have Internet sites and electronic chat rooms, through which patients and families give and receive information and advice, ask and answer questions, and obtain much needed emotional support. Similar disease-specific, self-help organizations are active in many nations around the world.

Determining Recurrence Risks

The estimation of recurrence risks is a central concern in genetic counseling. Ideally, it is based on knowledge of the genetic nature of the disorder in question and on the pedigree of the particular family being counseled. The family member whose risk for a genetic disorder is to be determined is usually a relative of a proband, such as a sibling of an affected child or a living or future child of an affected adult. In some families, especially for some autosomal dominant and X-linked traits, it may also be necessary to estimate the risk for more remote relatives.

When a disorder is known to have single-gene inheritance, the recurrence risk for specific family members can usually be determined from basic mendelian principles (Fig. 16-1; also see Chapter 7). On the other hand, risk calculations may be less than straightforward if there is reduced penetrance or variability of expression, or if the disease is frequently the result of new mutation, as in many X-linked and autosomal dominant disorders. Laboratory tests that give equivocal results can add further complications. Under these circumstances, mendelian risk estimates can sometimes be modified by means of applying conditional probability to the pedigree (see later), which takes into account information about the family that may increase or decrease the underlying mendelian risk.


FIGURE 16-1 Pedigree of a family with an autosomal recessive condition. The probability of being a carrier is shown beneath each individual symbol in the pedigree.

In contrast to single-gene disorders, the underlying mechanisms of inheritance for most chromosomal or genomic disorders and complex traits are unknown, and estimates of recurrence risk are based on previous experience (Fig. 16-2). This approach to risk assessment is valuable if there are reliable data on the frequency of recurrence of the disorder in families and if the phenotype is not heterogeneous. However, when a particular phenotype has an undetermined risk or can result from a variety of causes with different frequencies and with widely different risks, estimation of the recurrence risk is hazardous at best. In a later section, the estimation of recurrence risk in some typical clinical situations, both straightforward and more complicated, is considered.


FIGURE 16-2 Empirical risk estimates in genetic counseling. A family with no other positive family history has one child affected with a disorder known to be multifactorial or chromosomal. What is the recurrence risk? If the child is affected with spina bifida, the empirical risk to a subsequent child is approximately 4%. If the child has Down syndrome, the empirical risk for recurrence would be approximately 1% if the karyotype is trisomy 21, but it might be substantially higher if one of the parents is a carrier of a Robertsonian translocation involving chromosome 21 (see Chapter 6).

Risk Estimation by Use of Mendel's Laws When Genotypes Are Fully Known

The simplest risk estimates apply to families in which the relevant genotypes of all family members are known or can be inferred. For example, if both members of a couple are known to be heterozygous carriers of an autosomal recessive condition because they have a child with the disorder or because of carrier testing, the risk (probability) is one in four with each pregnancy that the child will inherit two mutant alleles and inherit the disease (Fig. 16-3A). Even if the couple were to have six unaffected children subsequent to the affected child (Fig. 16-3B), the risk in the eighth, ninth, or tenth pregnancy would still be one in four for each pregnancy (assuming there is no misattributed paternity for the first affected child).


FIGURE 16-3 Series of pedigrees showing autosomal recessive inheritance with contrasting recurrence risks. A and B, The genotypes of the parents are known. C, The genotype of the consultand's second partner is inferred from the carrier frequency in the population. D, The inferred genotype is modified by additional pedigree information. Arrows indicate the consultand. Numbers indicate recurrence risk in the consultand's next pregnancy.

Risk Estimation by Use of Conditional Probability When Alternative Genotypes Are Possible

In contrast to the simple case just described, situations arise in which the genotypes of the relevant individuals in the family are not definitively known; the risk for recurrence will be very different, depending on whether or not the consultand is a carrier of an abnormal allele of a disease gene. For example, the chance that a woman, who is known from her first marriage to be a carrier of cystic fibrosis (CF), might have an affected child depends on the chance that her husband by her second marriage is a carrier (Fig. 16-3C). The risk for the partner's being a carrier depends on his ethnic background (see Chapter 9). For the general non-Hispanic white population, this chance is approximately 1 in 22. Therefore the chance that a known carrier and her unrelated partner would have an affected first child is the product of these probabilities, or image × image = image (approximately 1.1%).

Of course, if the husband really were a carrier, the chance that the child of two carriers would be a homozygote or a compound heterozygote for mutant CF alleles is one in four. If the husband were not a carrier, then the chance of having an affected child is zero. Suppose, however, that one cannot test his carrier status directly. A carrier risk of 1 in 22 is the best estimate one can make for individuals of his ethnic background and no family history of CF without direct carrier testing; in fact, however, a person either is a carrier or is not. The problem is that we do not know. In this situation, the more opportunities the male in Figure 16-3C (who may or may not be a carrier of a mutant gene) has to pass on the mutant gene and fails to do so, the less likely it would be that he is indeed a carrier. Thus, if the couple were to come for counseling already with six children, none of whom is affected (Fig. 16-3D), it would seem reasonable, intuitively, that the husband's chance of being a carrier should be less than the 1 in 22 risk that the childless male partner in Figure 16-3C was assigned on the basis of the population carrier frequency. In this situation, we apply conditional probability (also known as Bayesian analysis, based on Bayes's theorem on probability published in 1763), a method that takes advantage of phenotypic information in a pedigree to assess the relative probability of two or more alternative genotypic possibilities and to condition the risk on the basis of that information. In Figure 16-3D, the chance that the second husband is a carrier is actually 1 in 119, and the chance that this couple would have a child with CF is therefore 1 in 476, not 1 in 88, as calculated in Fig. 16-3C. Some examples of the use of Bayesian analysis for risk assessment in pedigrees are examined in the following section.

Conditional Probability

To illustrate the application of Bayesian analysis, consider the pedigrees shown in Figure 16-4. In Family A, the mother II-1 is an obligate carrier for the X-linked bleeding disorder hemophilia A because her father was affected. Her risk for transmitting the mutant factor VIII (F8) allele responsible for hemophilia A is 1 in 2, and the fact that she has already had four unaffected sons does not reduce this risk. Thus the risk that the consultand (III-5) is a carrier of a mutant F8 allele is 1 in 2 because she is the daughter of a known carrier.


FIGURE 16-4 Modified risk estimates in genetic counseling. The consultands in the two families are at risk for having a son with hemophilia A. In Family A, the consultand's mother is an obligate heterozygote; in Family B, the consultand's mother may or may not be a carrier. Application of Bayesian analysis reduces the risk for being a carrier to only approximately 3% for the consultand in Family B but not the consultand in Family A. See text for derivation of the modified risk.

In Family B, however, the consultand's mother (individual II-2) may or may not be a carrier, depending on whether she has inherited a mutant F8 allele from her mother, I-1. If III-5 were the only child of her mother, III-5's risk for being a carrier would be 1 in 4, calculated as image (her mother's risk for being a carrier) × image (her risk for inheriting the mutant allele from her mother). Short of testing III-5 directly for the mutant allele, we cannot tell whether she is a carrier. In this case, however, the fact that III-5 has four unaffected brothers is relevant because every time II-2 had a son, the chance that the son would be unaffected is only 1 in 2 if II-2 were a carrier, whereas it is a near certainty (probability = 1) that the son would be unaffected if II-2 were, in fact, not a carrier at all. With each son, II-2 has, in effect, tested her carrier status by placing herself at a 50% risk for having an affected son. To have four unaffected sons might suggest that maybe her mother is not a carrier. Bayesian analysis allows one to take this kind of indirect information into account in calculating whether II-2 is a carrier, thus modifying the consultand's risk for being a carrier. In fact, as we show in the next section, her carrier risk is far lower than 50%.

Identify the Possible Scenarios

To translate this intuition into actual risk calculation, we use a Bayesian probability calculation. First, we list all possible alternative genotypes that may be present in the relevant individuals in the pedigree (Fig. 16-5). In this case, there are three scenarios, each reflecting a different combination of alternative genotypes:

A. II-2 is a carrier, but the consultand is not.

B. II-2 and the consultand are both carriers.

C. II-2 is not a carrier, which implies that the consultand could not be one either because there is no mutant allele to inherit.


FIGURE 16-5 Conditional probability used to estimate carrier risk for a consultand in a family with hemophilia in which the prior probability of the carrier state is determined by mendelian inheritance from a known carrier at the top of the pedigree. These risk estimates, based on genetic principles, can be further modified by considering information obtained from family history, carrier detection testing, or molecular genetic methods for direct detection of the mutation in the affected boy, with use of Bayesian calculations. A to C, The three mutually exclusive situations that could explain the pedigree.

Why do we not consider the possibility that the consultand is a carrier even though II-2 is not? We do not list this scenario because it would require that two mutations in the same gene occur independently in the same family, one inherited by the probands and one new mutation in the consultand, a scenario so vanishingly unlikely that it can be dismissed out of hand.

First, we draw the three possible scenarios as pedigrees (as in Fig. 16-5) and write down the probability of individual II-2's being a carrier or not. This is referred to as her prior probability because it depends simply on her risk for carrying a mutant allele inherited from her known carrier mother, I-1, and it has not been modified (“conditioned”) at all by her own reproductive history.

Next, we write down the probabilities that individuals III-1 through III-4 would be unaffected under each scenario. These probabilities are different, depending on whether II-2 is a carrier or not. If she is a carrier (situations A and B), then the chance that individuals III-1 through III-4 would all be unaffected is the chance that each did not inherit II-2's mutant F8 allele, which is 1 in 2 for each of her sons or (image)4 for all four. In situation C, however, II-2 is not a carrier, so the chance that her four sons would all be unaffected is 1 because II-2 does not have a mutant F8 to pass on to any of them. These are called conditional probabilitiesbecause they are probabilities affected by the condition of whether II-2 is a carrier.

Similarly, we can write down the probability that the consultand (III-5) is a carrier. In A, she did not inherit the mutant allele from her carrier mother, with a probability of 1 in 2. In B, she did inherit the mutant allele (probability = image). In C, her mother is not a carrier, and so III-5 has essentially a 100% chance of not being a carrier. Multiply the prior and conditional probabilities together to form the joint probabilitiesfor each situation, A, B, and C.

Finally, we determine what fraction of the total joint probability is represented by any scenario of interest; this is called the posterior probability of each of the three situations. Because III-5 is the consultand and wants to know her risk for being a carrier, we need the posterior probability of situation B, which is:


If we wish to know the chance that II-2 is a carrier, we add the posterior probabilities of the two situations in which she is a carrier, A and B, to get a carrier risk of 1 in 17, or approximately 6%.

If III-5 were also to have unaffected sons, her carrier risk could also be modified downward by a Bayesian calculation. However, if II-2 were to have an affected child, then she would have proved herself a carrier, and III-5's risk would thus become 1 in 2. Similarly, if III-5 were to have an affected child, then she must be a carrier, and Bayesian analysis would no longer be necessary.

Bayesian analysis may seem to some like mere statistical maneuvering. However, the analysis allows genetic counselors to quantify what seemed to be intuitively likely from inspection of the pedigree: the fact that the consultand had four unaffected brothers provides support for the hypothesis that her mother is not a carrier. The analysis having been performed, the final risk that III-5 is a carrier can be used in genetic counseling. The risk that her first child will have hemophilia A is image × image, or less than 1%. This risk is appreciably below the prior probability estimated without taking into account the genetic evidence provided by her brothers.

Conditional Probability in X-Linked Lethal Disorders

Because any severe X-linked disorder is manifested in the hemizygous male, an isolated case (no family history) of such a disorder may represent either a new gene mutation (in which case the mother is not a carrier) or inheritance of a mutant allele from his unaffected carrier mother; we do not consider the small but real chance of gonadal mosaicism for the mutation in the mother (see Chapter 7). Estimation of the recurrence risk depends on knowing the chance that she could be a carrier. Bayesian analysis can be used to estimate carrier risks in X-linked lethal diseases such as Duchenne muscular dystrophy (DMD) and severe ornithine transcarbamylase deficiency.

Consider the family at risk for DMD shown in Figure 16-6. The consultand, III-2, wants to know her risk for being a carrier. There are three possible scenarios, each with dramatically different risk estimates for the family:

A. III-1's condition may be the result of a new mutation. In this case, his sister and maternal aunt are not at significant risk for being a carrier.

B. His mother, II-1, is a carrier, but her condition is the result of a new mutation. In this case, his sister (III-2) has a 1 in 2 risk for being a carrier, but his maternal aunt is not at risk for being a carrier because his grandmother, I-1, is not a carrier.

C. His mother is a carrier who inherited a mutant allele from her carrier mother (I-1). In this case, all of the female relatives have either a 1 in 2 or a 1 in 4 risk for being carriers.


FIGURE 16-6 Conditional probability used to determine carrier risks for females in a family with an X-linked genetic lethal disorder in which the prior probability of being a carrier has to be calculated by assuming that the carrier frequency is not changing from generation to generation, and that the mutation rates are the same in males and females. Top, Pedigree of a family with an X-linked genetic lethal disorder. Bottom, The three mutually exclusive situations that could explain the pedigree. A, The proband is a new mutation. B, The mother of the proband is a new mutation. C, The mother of the proband inherited the mutation from her carrier mother, the grandmother of the proband.

How can we use conditional probability to determine the carrier risks for the female relatives of III-1 in this pedigree? If we proceed as we did previously with the hemophilia family in Figure 16-4, what do we use as the prior probability that individual I-1 is a carrier? We do not have pedigree information, as we did in the hemophilia pedigree, from which to calculate these prior probabilities. We can, however, use some simple assumptions that the frequency of the disease is unchanging and the new mutation rate is equal in males and females to estimate the prior probability (see Box).

Prior Probability That a Female in the Population is a Carrier of an X-Linked Lethal Disorder

Suppose H is the population frequency of female carriers of an X-linked lethal disorder. Assume H is constant from generation to generation.

Suppose the mutation rate at this X-linked locus in any one gamete = µ. Assume µ is the same in males and females. Mutation rate µ is a small number, in the range of 10−4 to 10−6 (see Chapter 4).

Then, there are three mutually exclusive ways that any female could be a carrier:

1. She inherits a mutant allele from a carrier mother = image × H.


2. She receives a newly mutant allele on the X she receives from her mother = µ.


3. She receives a newly mutant allele on the X she receives from her father = µ.

The chance a female is a carrier is the sum of the chance that she inherited a preexisting mutation and the chance that she received a new mutation from her mother or from her father.


Solving for H, you get the chance that a random female in the population is a carrier of a particular X-linked disorder = 4µ. Note that half of this 4µ, 2µ, is the probability she is a carrier by inheritance, and the other 2µ is the probability that she is a carrier by new mutation.

The chance a random female in the population is not a carrier is 1 − 4µ ≅ 1 (because µ is a very small number).

Now we can use this value 4µ from the Box as the prior probability that a woman is a carrier of an X-linked lethal disorder (see Fig. 16-6). For the purpose of calculating the chance that II-1 is a carrier, we ignore the female relatives II-3 and III-2 because there is nothing about them, such as phenotype, laboratory testing, or reproductive history, that conditions whether II-1 is a carrier.

• A. III-1 is a new mutation with probability µ. His mother and grandmother are both noncarriers, each of which has a probability of 1 − 4µ ≅ 1. The joint probability is µ × 1 × 1 = µ.

• B. I-1 is a noncarrier, and so II-1 must be the product of a maternal or paternal new mutation and not a carrier by inheritance because we are specifying in scenario B that I-1 is not a carrier. The chance that a female will be a carrier by new mutation only is µ + µ = 2µ (and not 4µ). The joint probability is therefore 2µ × image = µ.

• C. Individuals I-1 and II-1 are both carriers. As explained in the Box, the chance that I-1 is a carrier has a prior probability of 4µ. For II-1 to be a carrier, she must have inherited the mutant allele from her mother, which has probability 1 in 2. In addition, the chance that II-1 has passed the mutant allele on to her affected son is also 1 in 2. The joint probability is therefore 4µ × image × image = µ.

The posterior probabilities are now easy to calculate as µ/(µ + µ + µ) = image each for scenarios A, B, and C. The affected boy has a 1 in 3 chance of being affected because of a new mutation (situation A), whereas his mother II-1 is a carrier in both B and C and therefore has a image + image = image chance of being a carrier. The grandmother, I-1, is a carrier only in C, and so her chance of being a carrier is 1 in 3.

With these risk figures for the core individuals in the pedigree, we can then calculate the carrier risks for the female relatives II-3 and III-2. III-2's risk for being a carrier is image × [the chance II-1 is a carrier] = image × image = image. The risk that II-3 is a carrier is image × [the chance I-1 is a carrier] = image × image = image. In all of these calculations, for the sake of simplicity, we are ignoring the small but very real possibility of germline mosaicism (see Chapter 7). In a real genetic counseling situation, however, the possibility of mosaicism cannot be ignored.

Disorders with Incomplete Penetrance

To estimate the recurrence risk for disorders with incomplete penetrance, the probability that an apparently unaffected person actually carries the mutant gene in question must be considered. Figure 16-7 shows a pedigree of split hand deformity, an autosomal dominant abnormality with incomplete penetrance discussed in Chapter 7. An estimate of penetrance can be made from a single pedigree if it is large enough, or from a review of published pedigrees; we use 70% in our example. That means that a heterozygote for a mutation that causes split hand deformity has a 30% chance of not showing the phenotype. The pedigree shows several people who must carry the mutant gene but do not express it (i.e., in whom the defect is not penetrant), I-1 or I-2 (assuming no somatic or germline mosaicism) and II-3. The other unaffected family members may or may not carry the mutant gene.


FIGURE 16-7 Pedigree of family with split hand deformity and lack of penetrance in some individuals.

If III-4, the daughter of a known affected heterozygote, is the consultand, she either may have escaped inheriting the mutant allele from her affected mother or did inherit it but is not expressing the phenotype because penetrance is incomplete in this disorder. There are two possibilities (Fig. 16-8). In A, III-4 is not a carrier with prior probability of 1 in 2. If she does not carry the mutant allele, she will not have the phenotype, so the joint probability for A is 1 in 2. In B, III-4 is a carrier, also with prior probability 1 in 2. Here, we must apply the conditional probability that she is a carrier but does not show the phenotype, which has probability of 1 − penetrance = 1 − 0.7 = 0.3, so the joint probability for B is image × 0.3 = 0.15. The posterior probability that III-4 is a carrier without expressing the phenotype is therefore image = ≈23%.


FIGURE 16-8 Conditional probability calculation for the risk for the carrier state in the consultand in Figure 16-7. There are two possibilities: either she is not a carrier (A) or she is a carrier (B). Her failure to demonstrate the phenotype lowers her carrier risk from the prior probability of 1 in 2 (50%) to 3 in 13 (23%).

Disorders with Late Age at Onset

Many autosomal dominant conditions characteristically show a late age at onset, beyond the age of reproduction. Thus it is not uncommon in genetic counseling to ask whether a person of reproductive age who is at risk for a particular autosomal dominant disorder carries the gene. One example of such a disorder is a rare, familial form of Parkinson disease (PD) inherited as an autosomal dominant condition.

Consider the dominant PD pedigree in Figure 16-9 in which the consultand, an asymptomatic 35-year-old man, wishes to know his risk for PD. His prior risk for having inherited the PD gene from his affected grandmother is 1 in 4. Considering that perhaps only 5% of persons with this rare form of PD show symptoms at his age, he would not be expected to show signs of the disease even if he had inherited the mutant allele. The more significant aspect of the pedigree, however, is that the consultand's father (II-2) is also asymptomatic at the age of 60 years, an age by which perhaps two thirds of persons with this form of PD show symptoms and one third do not.


FIGURE 16-9 Age-modified risks for genetic counseling in dominant Parkinson disease. That the consultand's father is asymptomatic at the age of 60 years reduces the consultand's final risk for carrying the gene to approximately 12.5%. That the consultand himself is asymptomatic reduces the risk only slightly, because most patients carrying the mutant allele for this disorder will be asymptomatic at the age of 35 years.

As shown in Figure 16-10, there are three possibilities:

A. His father did not inherit the mutant allele, so the consultand is not at risk.

B. His father inherited the mutant allele and is asymptomatic at the age of 60 years, but the consultand did not.

C. His father inherited the mutant allele and is asymptomatic. The consultand inherited it from his father and is asymptomatic at the age of 35 years.


FIGURE 16-10 Three scenarios pertaining to the Parkinson disease pedigree in Figure 16-9. Individual II-2 is a nonpenetrant carrier (vertical line inside the symbol) in scenarios B and C. Individual III-1 is a nonpenetrant carrier in scenario C.

The father's chance of carrying the mutant allele (situations B and C) is 25%; the consultand's chance of having the mutant allele (situation C only) is 12%. Providing these recurrence risks in genetic counseling requires careful follow-up. If, for example, the consultand's father were to develop symptoms of PD, the risks would change dramatically.

Empirical Recurrence Risks

Counseling for Complex Disorders

Genetic counselors deal with many conditions that are not single-gene disorders. Instead, counselors may be called on to provide risk estimates for complex trait disorders with a strong genetic component and familial clustering, such as cleft lip and palate, congenital heart disease, meningomyelocele, psychiatric illness, and coronary artery disease (see Chapter 8). In these situations, the risk for recurrence in first-degree relatives of affected individuals may be increased over the background incidence of the disease in the population. For the vast majority of these disorders, however, we do not know the relevant underlying genetic variants or how they interact with each other or with the environment to cause disease.

As the information gained through the Human Genome Project is applied to the problem of diseases with complex inheritance, physicians and genetic counselors and other health professionals in the years ahead will have more of the information they need to provide accurate molecular diagnosis and risk assessment and to develop rational preventive and therapeutic measures. In the meantime, however, geneticists must rely on empirically derived risk figures to give patients and their relatives some answers to their questions about disease risk and how to manage that risk. Recurrence risks are estimated empirically by studying as many families with the disorder as possible and observing how frequently the disorder recurs. The observed frequency of a recurrence is taken as an empirical recurrence risk. With time, research should make empirical recurrence risks obsolete, replacing them with individualized assessments of risk based on knowledge of a person's genotype and environmental exposures.

Another area in which empirical recurrence risks must be applied is for chromosomal abnormalities (see Chapter 6). When one member of a couple is carrying a chromosomal or genome abnormality, such as a balanced translocation or a chromosomal inversion, the risk for a liveborn, chromosomally unbalanced child depends on a number of factors. These include the following:

• Whether the couple was ascertained through a previous liveborn, chromosomally abnormal child, in which case a viable offspring with the chromosome abnormality is clearly possible, or the ascertainment was through chromosome or genome studies for infertility or recurrent miscarriage

• The chromosomes involved, which region of the chromosome was affected, and the size of the regions that could be potentially trisomic or monosomic in the fetus

• Whether the mother or father is the carrier of the balanced translocation or inversion

These factors must all be considered when empirical recurrence risks are determined for a couple in which one member is carrying a balanced translocation or a seemingly “normal” genomic copy number variant.

Empirical recurrence risks are also applied when both parents are chromosomally normal but have a child with, for example, trisomy 21. In this case, the age of the mother plays a major role in that, in a young woman younger than 30 years, recurrence risk for trisomy 21 is approximately 5 per 1000 and the risk for any chromosome abnormality is approximately 10 per 1000 as opposed to the population risk of approximately 1.6 per 1000 live births. Over age 30, however, the age-specific risk becomes the dominant factor, and the fact of a previously affected child with trisomy 21 plays much less of a role in determining recurrence risk.

Genetic counselors must use caution in applying empirical risk figures to a particular family. First, empirical estimates are an average over what is undoubtedly a group of heterogeneous disorders with different mechanisms of inheritance. In any one family, the real recurrence risk may actually be higher or lower than the average. Second, empirical risk estimates use history to make predictions about future occurrences; if the underlying biological causes are changing through time, data from the past may not be accurate for the future.

For example, neural tube defects (myelomeningocele and anencephaly) occur in approximately 3.3 per 1000 live births in the U.S. white population. If, however, a couple has a child with a neural tube defect, the risk in the next pregnancy has been shown to be 40 per 1000 (13 times higher; see Table 8-9). The risks remained elevated compared with the general population risk for more distantly related individuals; a second-degree relative (e.g., a nephew or niece) of an individual with a neural tube defect was found to have a 1.7% chance of a similar birth defect. Thus, as we saw in Chapter 8, neural tube defects manifest many of the features typical of multifactorial inheritance. However, these empirical recurrence risks were calculated before widespread folic acid supplementation. With folate supplementation before conception and during early pregnancy, these recurrence risk figures have fallen dramatically (see Chapter 8). This is not because the allelic variants in the families have changed, but rather because a critical environmental factor has changed.

Finally, it is important to emphasize that empirical figures are derived from a particular population, and so the data from one ethnic group, socioeconomic class, or geographical location may not be accurate for an individual from a different background. Nonetheless, such figures are useful when patients ask genetic counselors to give a best estimate for recurrence risk for disorders with complex inheritance.

Genetic Counseling for Consanguinity

Consanguineous couples sometimes request genetic counseling before they have children because an increased risk for birth defects in their offspring is widely appreciated. In the absence of a family history for a known autosomal recessive condition, we use empirical risk figures for the offspring of consanguineous couples, based on population surveys of birth defects in children born to first-cousin couples compared with nonconsanguineous couples (Table 16-3).

TABLE 16-3

Incidence of Birth Defects in Children Born to Nonconsanguineous and First-Cousin Couples


Incidence of First Birth Defect in Sibship (per 1000)

Incidence of Recurrence of Any Birth Defect in Subsequent Children in Sibship (per 1000)

First-cousin marriage



Nonconsanguineous marriage



Data from Stoltenberg C, Magnus P, Skrondal A, Lie RT: Consanguinity and recurrence risk of birth defects: a population-based study, Am J Med Genet 82:424-428, 1999.

These results provide empirical risk figures in the counseling of first cousins. Although the relative risk for abnormal offspring is higher for related than for unrelated parents, it is still quite low: approximately double in the offspring of first cousins, compared with baseline risk figures for any abnormality of 15 to 20 per 1000 for any child, regardless of consanguinity. This increased risk is not exclusively for single-gene autosomal recessive diseases but includes the entire spectrum of single-gene and complex trait disorders. However, any couple, consanguineous or not, who has a child with a birth defect is at greater risk for having another child with a birth defect in a subsequent pregnancy.

These risk estimates for consanguinity may be slightly inflated given they are derived from communities in which first-cousin marriages are widespread and encouraged. These are societies in which the degree of relationship (coefficient of inbreeding) between two first cousins may actually be greater than the theoretical image due to multiple other lines of relatedness (see Chapter 9). Furthermore, these same societies may also limit marriages to individuals from the same clan, leading to substantial population stratification, which also increases the rate of autosomal recessive disease beyond what might be expected based on mutant allele frequency alone (see Chapter 9).

Molecular and Genome-Based Diagnostics

Advances over the past few years in mutation detection have provided major improvements in risk assessment, carrier detection, and prenatal diagnosis, in many cases allowing determination of the presence or absence of particular mutations with essentially 100% accuracy. Laboratory testing for direct detection of disease-causing mutations is now available for more than 3000 genes involved in well over 4000 genetic conditions. With our expanding knowledge of the genes involved in hereditary disease and the rapidly falling cost of DNA sequencing, direct detection of mutations in a patient's or family member's genomic DNA to make a molecular diagnosis has become standard of care for many conditions. DNA samples for analysis are available from such readily accessible tissues as a buccal scraping or blood sample, but also from tissues obtained by more invasive testing, such as chorionic villus sampling or amniocentesis (see Chapter 17).

Mutation detection is most commonly performed using one of two different techniques, depending on the nature of the mutations in question. Comprehensive sequencing of polymerase chain reaction (PCR) products made from the coding regions and splice sites immediately adjacent to coding exons is effective when the mutation is a single nucleotide variant or small insertion or deletion. However, when the mutation is a large deletion involving one or more exons, attempts to sequence PCR products made from primers that fall into the deleted region is highly problematic. The sequencing will simply fail if the deletion is in an X-linked gene in a male or, even worse, can be misleading because it will yield only the sequence from the other copy of the gene on the homologous autosome. Duplications are even more challenging because they may yield a perfectly normal sequence unless the primers used for amplification happen to straddle the junction of a duplicated segment. For deletions and duplications, a variety of other methods are available that detect deletions or duplications by providing a quantitative measure of the copy number of the deleted or duplicated region.

For most genetic conditions, the majority of pathogenic mutations are single nucleotide or small insertion/deletion mutations that are well detected by sequencing. One major exception is DMD, in which point mutations or small insertions or deletions account for only approximately 34% of mutations, whereas large deletions and insertions account for 60% and 6%, respectively, of the mutations in patients with DMD. In a patient with DMD, one might start with measuring the copy number of segments of DNA across the entire gene to look for deletion or duplication and, if normal, consider sequencing.

Gene Panels and “Clinical Whole Exomes”

For many hereditary disorders (including hereditary retinal degeneration, deafness, hereditary breast and ovarian cancer, congenital myopathy, mitochondrial disorders, familial thoracic aortic aneurysm syndrome, and hypertrophic or dilated cardiomyopathies), there is substantial locus heterogeneity, that is, a large number of genes are known to be mutated in different families with these disorders. When faced with an individual patient with one of these highly heterogeneous disorders in whom the particular gene and mutations responsible for the disorder are not known, recent advances in DNA sequencing make it possible to analyze large panels of dozens to well over 100 genes simultaneously and cost-effectively for mutations in every gene in which mutations have been seen previously to cause the disorder.

In disorders for which even a large panel of relevant genes cannot be formulated for a particular phenotypically defined disorder, diagnosis might still be possible by analyzing the coding exons of every gene (i.e., by whole-exome sequencing) or by sequencing the entire genome in a search for disease-causing mutations (see Chapter 4). For example, two reported series of so-called clinical whole exome testing, one from the United States and one from Canada, showed substantial success. In a 2013 study from the United States, 250 patients with primarily undiagnosed neurological disorders underwent whole-exome sequencing and 62 (≈25%) received a diagnosis. Interestingly, among the patients receiving a diagnosis, four were likely to have had two disorders at the same time, which made a clinical diagnosis very difficult because the patients' phenotype did not match any single known disorder. In another study in 2014 by the Canadian FORGE Consortium, approximately 1300 patients representing 264 disorders known or suspected of being hereditary, but for which the genes involved were unknown, underwent whole-exome sequencing. Mutations highly likely to explain the disorders were found in 60%; at least half of the genes had not been previously known to be involved in human disease. Of great interest in both studies was that a large number of patients carried de novo disease-causing mutations in genes not previously suspected of causing disorders. These mutations, because they are de novo, are extremely difficult to find by standard gene discovery methods as described in Chapter 10, such as linkage or association, and therefore pose particular challenges for genetic counseling and risk assessment.

Variant Interpretation and “Variants of Unknown Significance”

The use of large gene panels and, even more so, whole-exome or whole-genome sequencing raises special issues for sequence interpretation and risk assessment. As the number of genes being studied increases, the number of differences between an individual's sequence and that of an arbitrary reference sequence also increases; consequently many previously undescribed variants will be found whose pathogenetic significance is unknown. These are referred to as “variants of unknown significance” (VUSs). This is particularly the case for missense mutations that result in the substitution of one amino acid for another in the encoded protein.

Interpreting variants is a challenging and demanding area for all professional geneticists engaged in providing molecular diagnostic services. The American College of Medical Genetics and Genomics has recommended that variants be assigned into one of five categories, ranging from definitely pathogenic to definitely benign (see Box). Only those variants with a high probability of being disease-causing are communicated to the medical provider and patient. It is a matter of debate whether a record of all VUSs should be retained by the testing laboratory and attached to a patient's record, thereby remaining available for updating as new information becomes available to allow reclassification as either benign or pathogenic. Thus risk assessment and genetic counseling in this context are ongoing and iterative processes, continually evaluating newly available information and communicating this to medical providers and patients as appropriate.

Assessing the Clinical Significance of a Gene Variant

The American College of Genetics and Genomics recommends that all variants detected during gene sequencing (whether from targeted, whole-exome, or whole-genome sequencing) be classified on a five-level scale, spanning pathogenic, likely pathogenic, of uncertain significance, likely benign, and benign variants. Specialists in molecular diagnostics, human genomics, and bioinformatics have developed a series of criteria for assessing where a mutation sits among these five categories. In the vast majority of cases, none of these criteria is absolutely definitive but must be considered together to provide an overall assessment of how likely any variant is to be pathogenic. These criteria include the following:

• Population frequency—If a variant has been seen frequently in a sizeable fraction of normal individuals (>2% of the population), it is considered less likely to be disease causing. Being frequent is, however, no guarantee a variant is benign because autosomal recessive conditions or disorders with low penetrance may be due to a disease-causing variant that may be surprisingly common among unaffected individuals because most carriers will be asymptomatic. Conversely, the vast majority of variants (>98%) found when sequencing a large gene panel or in a whole-exome or whole-genome sequence are rare (occur in 1% of the population or less), so being rare is no guarantee it is disease causing!

• In silico assessment—There are many software tools designed to evaluate how likely a missense variant is to be pathogenic by determining if the amino acid at that position is highly conserved or not in orthologous proteins in other species and how likely it is that a particular amino acid substitution would be tolerated. Such tools are less than precise and are generally never used by themselves for categorizing variants for clinical use. They are, however, improving with time and are playing a role in variant assessment. A comparable set of bioinformatic tools is being developed to assess the pathogenicity of other types of variants, such as potential splice site variants or even noncoding sequence variants.

• Functional data—If a particular variant has been shown to affect in vitro biochemical activity, a function in cultured cells, or the health of a model organism, then it is less likely to be benign. However, it remains possible that a particular variant will appear benign by these criteria and still be disease-causing in humans because of a prolonged human life span, environmental triggers, or compensatory genes in the model organism not present in humans.

• Segregation data—If a particular variant has been seen to be coinherited with a disease in one or more families, or, conversely, does not track with a disease in the family under investigation, then it is more or less likely to be pathogenic. Of course, when only a few individuals are affected, the variant and disease may appear to track by random chance; the number of times a variant and disease must be coinherited to be considered not by chance alone is not firmly fixed but is generally accepted to be at least 5, if not 10. Finding affected individuals in the family who do not carry the variant would be strong evidence against the variant being pathogenic, but finding unaffected individuals who do carry the variant is less persuasive if the disorder is known to have reduced penetrance.

• De novo mutation—The appearance of a severe disorder in a child along with a new mutation in a coding exon that neither parent carries (de novo mutation) is additional evidence the variant is likely to be pathogenic. However, between 1 and 2 new mutations occur in the coding regions of genes in every child (see Chapter 4), and so the fact that a mutation is de novo is not definitive for the mutation being pathogenic.

• Variant characterization—A variant may be a synonymous change, a missense mutation, a nonsense mutation, a frameshift with a premature termination downstream, or a highly conserved splice site mutation. The impact on the function of the gene can be inferred but, once again, is not definitive. For example, a synonymous change that does not change an amino acid codon might be thought to be benign but may have deleterious effects on normal splicing and be pathogenic (see examples in Chapter 12). Conversely, premature termination or frameshift mutations might be considered to be always deleterious and disease causing. However, such mutations occurring at the far 3′ end of a gene may result in a truncated protein that is still quite capable of functioning and therefore be a benign change.

• Prior occurrence—A variant that has been seen before multiple times in affected patients, as recorded in collections of variants found in patients with a similar disorder, is important additional evidence for the variant being pathogenic. Even if a missense variant is novel, that is, has never been described before, it is more likely to be pathogenic if it occurs at the same position in the protein where other known pathogenic missense mutations have occurred.

Another important aspect of how to use molecular and genome-based diagnostic testing in families is the selection of the best person(s) to test. If the consultand is also the affected proband, then molecular testing is appropriate. If, however, the consultand is an unaffected, at-risk individual, with an affected relative serving as the indication for having genetic counseling, it is best to test the affected person rather than the consultand, if logistically possible. This is because a negative mutation test in the consultand is a so-called uninformative negative; that is, we do not know if the test was negative because (1) the gene or mutation responsible for disease in the proband was not covered by the test, or (2) the consultand in fact did not inherit a variant that we could have detected had we found the disease-causing variant in the affected proband in the family. Once the mutation or mutations responsible for a particular disorder are found in the proband, then the other members of the family no longer need comprehensive gene sequencing. The DNA of family members can be assessed with less expensive testing only for the presence or absence of the specific mutations already found in the family. If a family member tests negative under these circumstances, the test is a “true” negative that eliminates any elevated risk due to his or her having an affected relative.

General References

Buckingham L. Molecular diagnostics: fundamentals, methods and clinical applications. ed 2. F.A. Davis and Co: Philadelphia; 2011.

Gardner RJM, Sutherland GR, Shaffer LG. Chromosome abnormalities and genetic counseling. ed 4. Oxford University Press: Oxford; 2011.

Harper PS. Practical genetic counseling. ed 7. Hodder Arnold: London; 2010.

Uhlmann WR, Schuette JL, Yashar B. A guide to genetic counseling. Wiley-Blackwell: New York; 2009.

Young ID. Introduction to risk calculation in genetic counseling. ed 3. Oxford University Press: New York; 2007.

References for Specific Topics

Beaulieu CL, Majewski J, Schwartzentruber J, et al. FORGE Canada Consortium: Outcomes of a 2-year national rare-disease gene-discovery project. Am J Hum Genet. 2014;94:809–817.

Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370:2418–2425.

Brock JA, Allen VM, Keiser K, et al. Family history screening: use of the three generation pedigree in clinical practice. J Obstet Gynaecol Can. 2010;32:663–672.

Guttmacher AE, Collins FS, Carmona RH. The family history—more important than ever. N Engl J Med. 2004;351:2333–2336.

Richards CS, Bale S, Bellissimo DB, et al. ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med. 2008;10:294–300.

Sheridan E, Wright J, Small N, et al. Risk factors for congenital anomaly in a multiethnic birth cohort: an analysis of the Born in Bradford study. Lancet. 2013;382:1350–1359.

Yang Y, Muzny DM, Reid JG, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med. 2013;369:1502–1511.

Zhang VW, Wang J. Determination of the clinical significance of an unclassified variant. Methods Mol Biol. 2012;837:337–348.


1. You are consulted by a couple, Dorothy and Steven, who tell the following story. Dorothy's maternal grandfather, Bruce, had congenital stationary night blindness, which also affected Bruce's maternal uncle, Arthur; the family history appears to fit an X-linked inheritance pattern. (There is also an autosomal dominant form.) Whether Bruce's mother was affected is unknown. Dorothy and Steven have three unaffected children: a daughter, Elsie, and two sons, Zack and Peter. Elsie is planning to have children in the near future. Dorothy wonders whether she should warn Elsie about the risk that she might be a carrier of a serious eye disorder. Sketch the pedigree, and answer the following.

a. What is the chance that Elsie is heterozygous?

b. An ophthalmologist traces the family history in further detail and finds evidence that in this pedigree, the disorder is not X-linked but autosomal dominant. There is no evidence that Dorothy's mother Rosemary was affected. On this basis, what is the chance that Elsie is heterozygous?

2. A deceased boy, Nathan, was the only member of his family with Duchenne muscular dystrophy (DMD). He is survived by two sisters, Norma (who has a daughter, Olive) and Nancy (who has a daughter, Odette). His mother, Molly, has two sisters, Maud and Martha. Martha has two unaffected sons and two daughters, Nora and Nellie. Maud has one daughter, Naomi. No carrier tests are available because the mutation in the affected boy remains unknown.

a. Sketch the pedigree, and calculate the posterior risks for all these females, using information provided in this chapter.

b. Suppose prenatal diagnosis by DNA analysis is available only to women with more than a 2% risk that a pregnancy will result in a son with DMD. Which of these women would not qualify?

3. In a village in Wales in 1984, 13 boys were born in succession before a girl was born. What is the probability of 13 successive male births? What is the probability of 13 successive births of a single sex? What is the probability that after 13 male births, the 14th child will be a boy?

4. Let H be the population frequency of carriers of hemophilia A. The incidence of hemophilia A in males (I) equals the chance that a maternal F8 gene has a new mutation (µ) from a noncarrier mother plus the chance it was inherited as a preexisting mutation from a carrier mother (image × H). Adding these two terms gives I = µ + (image × H). H is the chance a carrier inherits the mutation from a surviving, reproducing affected father (I × f) (where f is the fitness of hemophilia) plus the chance of a new paternal mutation (µ) plus the chance of a new maternal mutation (µ) plus the chance of inheriting it from a carrier mother (image × H). Adding these four terms gives H = (I × f) + µ + µ + (image)H.

a. If hemophilia A has a fitness (f) of approximately 0.70, that is, hemophiliacs have approximately 70% as many offspring as do controls, then what is the incidence of affected males? of carrier females? (Answer in terms of multiples of the mutation rate.) If a woman has a son with an isolated case of hemophilia A, what is the risk that she is a carrier? What is the chance that her next son will be affected?

b. For DMD, f = 0. What is the population frequency of affected males? Of carrier females?

c. Color blindness is thought to have normal fitness (f = 1). What is the incidence of carrier females if the frequency of color blind males is 8%?

5. Ira and Margie each have a sibling affected with cystic fibrosis.

a. What are their prior risks for being carriers?

b. What is the risk for their having an affected child in their first pregnancy?

c. They have had three unaffected children and now wish to know their risk for having an affected child. Using Bayesian analysis to take into consideration that they have already had three unaffected children, calculate the chance that their next child will be affected.

6. A 30-year-old woman with myotonic dystrophy comes in for genetic counseling. Her son, aged 14 years, shows no symptoms, but she wishes to know whether he will be affected with this autosomal dominant condition later in life. Approximately half of individuals carrying the mutant gene are asymptomatic before the age of 14 years. What is the risk that the son will eventually develop myotonic dystrophy? Should you test the child for the expanded repeat in the gene for myotonic dystrophy?

7. A couple arrives in your clinic with their 7-month-old son, who has been moderately developmentally delayed from birth. The couple is contemplating having additional children, and you are asked whether this could be a genetic disorder.

a. Is this possible, and if so, what pattern or patterns of inheritance would fit this story?

b. On taking a detailed family history, you learn that both parents' families were originally from the same small village in northern Italy. How might this fact alter your assessment of the case?

c. You next learn that the mother has two sisters and five brothers. Both sisters have developmentally delayed children. How might this alter your assessment of the case?

8. You are addressing a Neurofibromatosis Association parents' meeting. A severely affected woman, 32 years old, comments that she is not at risk for passing on the disorder because her parents are not affected, and her neurofibromatosis therefore is due to a new mutation. Comment.

9. The figure shows the family from Figure 16-6, but with additional information that the consultand III-2 has two unaffected sons. There are now seven possible scenarios to explain this pedigree. List the scenarios, and use them to calculate the carrier risk for individual III-2.


The family from Figure 16-6 but now with additional information consisting of unaffected males that must be used to modify the carrier risks for females in the pedigree.

10. An alternative approach to calculating the carrier risk for III-2 (refer to pedigree in problem 9) is to break the pedigree apart and do the calculations stepwise, a method referred to as the dummy consultand method. Instead of calculating the joint probabilities of all seven scenarios to determine the posterior probability that III-2 is a carrier, one ignores III-2 and her two children for the moment, makes individual II-1 serve as a dummy consultand, and calculates II-1's risk for being a carrier without using any conditional information provided by III-2. Then, with the carrier risk for II-1 in hand, determine the prior probability that III-2 is a carrier and then condition that risk by use of the fact that she has two unaffected male children. How does the carrier risk for III-2 calculated by the dummy consultand method compare with the risk calculated by the comprehensive method in Table 16-3? How about the carrier risk for II-1? How does the risk calculated by the dummy consultand method compare with the risk calculated by the comprehensive method in Table 16-3?