A disorder is said to show genetic heterogeneity if it can be caused by more than one genetic mechanism (p. 346). Many such disorders are recognized, and counseling can be extremely difficult if the heterogeneity extends to different modes of inheritance. Commonly encountered examples include the various forms of Ehlers-Danlos syndrome (Figure 17.1), Charcot-Marie-Tooth disease (p. 296), and retinitis pigmentosa, all of which can show autosomal dominant, autosomal recessive, and X-linked recessive inheritance (Table 17.1). Fortunately, progress in molecular genetics is providing solutions to many of these problems. For example, mutations in the gene that codes for rhodopsin, a retinal pigment protein, are found in approximately 30% of families showing autosomal dominant inheritance of retinitis pigmentosa (Figure 17.2) and the molecular basis of the most common forms of Charcot-Marie-Tooth disease (type 1), also known as hereditary motor and sensory neuropathy, is now understood (p. 296).

FIGURE 17.1 Ehlers-Danlos syndrome. The inheritance pattern in this case is autosomal dominant because father and son are affected.

Table 17.1 Hereditary Disorders that can Show Different Patterns of Inheritance

Disorder	Inheritance Patterns
Cerebellar ataxia	AD, AR
Charcot-Marie-Tooth disease	AD, AR, XR
Congenital cataract	AD, AR, XR
Ehlers-Danlos syndrome	AD, AR, XR
Ichthyosis	AD, AR, XR
Microcephaly	AD, AR
Polycystic kidney disease	AD, AR
Retinitis pigmentosa	AD, AR, XR, M
Sensorineural hearing loss	AD, AR, XR, M

AD, Autosomal dominant; AR, autosomal recessive; XR, X-linked recessive; M, mitochondrial.

FIGURE 17.2 Fundus showing typical pigmentary changes of retinitis pigmentosa.

Calculating and Presenting the Risk

In some counseling situations, calculation of the recurrence risk is relatively straightforward and requires little more than a reasonable knowledge of mendelian inheritance. However, many factors, such as delayed age of onset, reduced penetrance, and the use of linked DNA markers, can result in the calculation becoming much more complex. The theoretical aspects of risk calculation are considered in more detail in Chapter 22.

The provision of a recurrence risk does not simply involve conveying a stark risk figure in isolation. It is very important that the information provided is understood, and that parents are given as much background information as possible to help them reach their own decision. As a working rule of thumb, recurrence risks should be quantified, qualified, and placed in context.

Quantification—The Numerical Value of a Risk

Most prospective parents will be familiar to some degree with the concept of risk, but not everyone is comfortable with probability theory and the alternative ways of expressing risk, such as in the form of odds or as a percentage. Thus, for example, a risk of 1 in 4 can be presented as an odds ratio of 3 to 1 against, or numerically as 25%. Consistency and clarity are important if confusion is to be avoided. It is also essential to emphasize that a risk applies to each pregnancy and that chance does not have a memory. For example, that parents have just had a child with an autosomal recessive disorder (recurrence risk of 1 in 4) does not mean that their next three children will be unaffected. A useful analogy is that of the tossed coin that cannot be expected to remember whether it landed heads or tails at the last throw and cannot therefore be expected to know what it should do at the next throw.

It is also important that genetic counselors should not be seen exclusively as prophets of doom. Continuing the penny analogy, the good side of the coin should also be emphasized, particularly if the odds strongly favor a successful outcome. For example, a couple faced with a probability of 1 in 25 that their next baby will have a neural tube defect should be reminded that there are 24 chances of 25 that their next baby will not be affected.

Qualification—The Nature of a Risk

Several studies have indicated that the most important factor determining the decision parents make about extending their family is the nature of the long-term burden (severity) of disease (or health care) associated with a risk, rather than its precise numerical value. Therefore a ‘high’ risk of 1 in 2 for a trivial problem such as an extra digit (polydactyly) will deter very few parents. In contrast a ‘low’ risk of 1 in 25 for a disabling condition such as a neural tube defect can have a very significant deterrent effect. A woman who grew up watching her brother develop Duchenne muscular dystrophy and subsequently die from the condition as a young adult may not risk having children even if there is only a 1% chance that she is a carrier. Other factors, such as whether a condition can be treated successfully, whether it is associated with pain and suffering, and whether prenatal diagnosis is available, may all be relevant to the decision-making process.

Placing Risks in Context

Prospective parents seen at a genetic counseling clinic should be provided with information that enables them to put their risks in context so as to be able to decide for themselves whether a risk is ‘high’ or ‘low’. For example, it can be helpful (but also alarming) to point out that approximately 1 in 40 of all babies has a congenital malformation (often treatable) or handicapping disorder. Therefore, an additional quoted risk of 1 in 50, although initially alarming, might on reflection be perceived as relatively low. As an arbitrary guide, risks of 1 in 10 or greater tend to be regarded as high, 1 in 20 or less as low, and intermediate values as moderate.

Discussing the Options

Having established the diagnosis and discussed the risk of occurrence/recurrence, the counselor is then obliged to ensure that the consultands are provided with all of the information necessary for them to make their own informed decisions. This should include details of all the choices open to them. For example, if relevant, the availability of prenatal diagnosis should be discussed, together with details of the techniques, limitations and risks associated with the various methods employed (see Chapter 21). Mention will sometimes be made of other reproductive options. These can include alternative approaches to conception, such as artificial insemination using donor sperm, the use of donor ova and preimplantation genetic diagnosis (p. 335). These techniques can be used when one partner is infertile, as in the case of Klinefelter syndrome and Turner syndrome (see Chapter 18), or simply to bypass the possibility that one or other partner will transmit his or her disadvantageous gene(s) to the baby.

These are issues that should be broached with great care and sensitivity. For some couples, the prospect of prenatal diagnosis followed by selective termination of pregnancy is unacceptable, whereas others view this as their only means of ensuring that they have healthy children. Whatever the personal views of the counselor, the consultands are entitled to knowledge of prenatal diagnostic procedures that are technically feasible and legally permissible.

Communication and Support

The ability to communicate is essential in genetic counseling. Communication is a two-way process. Not only does the counselor provide information, he or she also has to be receptive to the fears and aspirations, expressed or unexpressed, of the consultand. A readiness to listen is a key attribute for anyone involved in genetic counseling, as is an ability to present information in a clear, sympathetic, and appropriate manner.

Often an individual or couple will be extremely upset when first made aware of a genetic diagnosis, and it is very common for guilt feelings to set in. The individual or couple may look back and scrutinize every event and happening, for example during a pregnancy. The delivery of potentially distressing information cannot be carried out in isolation. Genetic counselors need to take into account the complex psychological and emotional factors that can influence the counseling dialog. The setting should be agreeable, private, and quiet, with ample time for discussion and questions. When possible, technical terms should be avoided or, if used, fully explained. Questions should be answered openly and honestly, and if information is lacking it is certainly not a fault or sign of weakness to admit that this is so. Most couples respect and recognize the truth, and some parents of children whose condition cannot be diagnosed derive a curious pleasure from knowing that their child appears to be unique and has bamboozled the medical profession (unfortunately, this is not particularly difficult!).

Despite all of these measures, a counseling session can be so intense and intimidating that the amount and accuracy of information retained can be very limited. For this reason, a letter summarizing the topics discussed at a counseling session is usually sent to the family afterwards. In addition, they are sometimes contacted later by a member of the counseling team, thereby providing an opportunity for clarification of any confusing issues and for further questions to be answered.

It is poor practice to simply convey information of a distressing nature without offering an opportunity for further discussion and long-term support. Most genetic counseling centers maintain informal contact with relevant families through a network of genetic nurse counselors who are familiar with the family and their particular circumstances. This is especially valuable for prospective parents who subsequently request specific prenatal diagnostic investigations, and for presymptomatic adults who are shown to be at high risk of developing late-onset autosomal dominant disorders such as Alzheimer disease (p. 342) and Huntington disease (p. 293). Genetic registers (p. 332) provide a useful means of ensuring that effective contact can be maintained with all such relevant family members.

Patient Support Groups

Finally, mention should be made of the widespread network of support groups that now exists. These organizations have usually been established by highly motivated and well-informed parents or affected families who can provide enormous support and companionship for others affected by a particular genetic condition or syndrome. When confronted by a new diagnosis of a rare disorder, many families feel very isolated; if at all possible they should be given contact information so that they have the option of communicating with other affected families who have had similar experiences. Referral to an appropriate support group would now be viewed as an essential integral component of the genetic counseling process. As well as providing support and information for affected families, these groups have often been very successful, not only in fostering (and funding) research but also in developing new services.

Genetic Counseling—Directive or Non-Directive?

It has already been emphasized that genetic counseling should be viewed as a communication process that provides information. The ultimate goal is to ensure that an individual or couple can reach their own decisions based on full information about risks and options. There is universal agreement that genetic counseling should be non-directive, with no attempt being made to steer the consultand along a particular course of action. In the same spirit the genetic counselor should also strive to be non-judgmental, even if a decision is reached that seems ill advised or is contrary to the counselor’s own beliefs. Thus the role of the genetic counselor is to facilitate and enhance individual autonomy rather than to give advice or recommend a particular course of action. This person-centered approach conforms most closely to the model of counseling theory developed by the American, Carl Rogers (1902–1987), rather the psychodynamic approach of Sigmund Freud (1856–1939).

Genetic counselors are sometimes asked what they themselves would do if placed in the consultand’s position. Generally it is preferable to avoid being drawn into expressing an opinion, opting instead to suggest that the consultand try to imagine how he or she might feel in the future having pursued each of the available options. This approach, sometimes referred to as ‘scenario-based decision counseling’, provides individuals with an opportunity for careful reflection. This is particularly important if one of the options under consideration involves a potentially irreversible reproductive decision such as sterilization. There is a well-established maxim that it is the consultands and not the counselors who have to live with the consequences of their decisions and, indeed, consultands should be encouraged to make the decision that they can best live with—the one that they are least likely to regret.

Outcomes in Genetic Counseling

The issue of defining outcomes in genetic counseling is difficult and contentious, but also topical in today’s climate of health economy where everything has to be justified. The difficulty arises because of the rather nebulous nature of genetic counseling, which, in contrast to most medical activities, does not have any easily quantified end points, such as rate of infection or survival after surgery. The issue is topical because of pressure from funding authorities, with emphasis on demonstrable quality and effectiveness. Finally, the issue is contentious because it raises serious questions about the purpose of genetic counseling and whether this should be viewed as simply the provision of information or whether there should be identified benefits for society in terms of a reduction in the incidence of genetic disease.

In practice the three main outcome measures that have been assessed are recall, impact on subsequent reproductive behavior, and patient satisfaction. Most studies have shown that the majority of individuals who have attended a genetic counseling clinic have a reasonable recall of the information given, particularly if this was reinforced by a personal letter or follow-up visit. Nevertheless, confusion can arise, and as many as 30% of counselees have difficulty in remembering a precise risk figure. Studies that have focused on the subsequent reproductive behavior of couples that have attended a genetic counseling clinic have shown that approximately 50% have been influenced to some extent. The factors that have been shown to be influential are the severity of the disorder, the desire of the parents to have children, and whether prenatal diagnosis and/or treatment are available. Finally, studies that have attempted to assess patient satisfaction have struggled to address the problem of how this should best be defined. For example, an individual could be very satisfied with the way in which they were counseled but remain very dissatisfied by lack of a precise diagnosis or the availability of subsequent prenatal diagnostic tests.

In an increasingly cost-conscious society, it is not surprising that the purchasers of health care, whether private or state funded, are keen to identify quantifiable targets with which they can assess the ‘effectiveness’ of genetics services, and genetic counseling in particular. Outcomes such as the number of abnormal pregnancies terminated or individuals screened can seem attractive to administrators and politicians who are preoccupied with balancing budgets and cost–benefit analyses. In contrast, clinical geneticists and non-medical counselor colleagues universally reject the use of these outcome criteria on the grounds that they hint at a eugenics philosophy that is totally unacceptable in a society in which patient autonomy is a guiding ethical principle. Instead, they emphasize the benefits of an educated informed community with enhanced individual autonomy. The goals of satisfaction as expressed by the users of genetic services and their ability to make informed decisions are seen as much more acceptable than a reduction in the financial and personal burdens caused by genetic disease.

In the future, it is possible that an outcome measure such as ‘perceived personal control’ will be developed. This will almost certainly incorporate both information and satisfaction criteria, together with an assessment of whether individuals have been able to understand the information and come to terms with their situation, thereby enabling them to make appropriate life decisions with which they are comfortable. The idea is also consistent with general government policy to encourage individuals to take more personal control of their own health agenda.

Special Problems in Genetic Counseling

There are a number of special problems that can arise in genetic counseling.

Consanguinity

A consanguineous relationship is one between blood relatives who have at least one common ancestor no more remote than a great-great-grandparent. Consanguineous marriage is widespread in many parts of the world (Table 17.2). In Arab populations, the most common type of consanguineous marriage occurs between first cousins who are the children of two brothers, whereas in the Indian subcontinent uncle–niece marriages are the most commonly encountered form of consanguineous relationship. Although there is in these communities some recognition of the potential disadvantageous genetic effects of consanguinity, there is also a strongly held view that these are greatly outweighed by social advantages such as greater family support and marital stability.

Table 17.2 Worldwide Incidence of Consanguineous Marriage

Country	Incidence (%)
Kuwait	54
Saudi Arabia	54
Jordan	50
Pakistan	40–50
India	5–60
Syria	33
Egypt	28
Lebanon	25
Algeria	23
Japan	2–4
France, UK, USA	2

Data adapted from various sources including Jaber L, Halpern GJ, Shohat M 1998 The impact of consanguinity worldwide. Commun Genet 1:12–17.

Many studies have shown that among the offspring of consanguineous marriages, there is an increased incidence of both congenital malformations and other conditions that will present later, such as hearing loss and mental retardation. For the offspring of first cousins, the incidence of congenital malformations is increased to approximately twice that seen in the offspring of unrelated parents. Almost all of this increase in morbidity and mortality is attributed to homozygosity for autosomal recessive disorders, a finding consistent with Garrod’s original observation that ‘the mating of first cousins gives exactly the conditions most likely to enable a rare, and usually recessive, character to show itself’ (p. 113).

On the basis of studies of children born to consanguineous parents, it has been estimated that the average human carries between one and two genes for a harmful autosomal recessive disorder, together with several mutations for conditions that result in lethality before birth. Most prospective consanguineous parents are concerned primarily with the risk that they will have a handicapped child, and fortunately the overall risks are usually relatively small. When estimating a risk for a particular consanguineous relationship, it is generally assumed that each common ancestor carried one deleterious recessive mutation.

Therefore, for first cousins, the probability that their first child will be homozygous for their common grandfather’s deleterious gene will be 1 in 64 (Figure 17.3). Similarly, the risk that this child will be homozygous for the common grandmother’s recessive gene will also be 1 in 64. This gives a total probability that the child will be homozygous for one of the grandparent’s deleterious genes of 1 in 32. This risk should be added to the general population risk of 1 in 40 that any baby will have a major congenital abnormality (p. 249), to give an overall risk of approximately 1 in 20 that a child born to first-cousin parents will be either malformed or handicapped in some way. Risks arising from consanguinity for more distant relatives are much lower.

FIGURE 17.3 Probability that the first child of first cousins will be homozygous for the deleterious allele (*) carried by the common great-grandfather. A similar risk of 1 in 64 will apply to the deleterious allele belonging to the common great-grandmother, giving a total risk of 1 in 32.

For consanguineous marriages, there is also a slightly increased risk that a child will have a multifactorial disorder. In practice this risk is usually very small. In contrast, a close family history of an autosomal recessive disorder can convey a relatively high risk that a consanguineous couple will have an affected child. For example, if the sibling of someone with an autosomal recessive disorder marries a first cousin, the risk that their first baby will be affected equals 1 in 24 (p. 342).

Incest

Incestuous relationships are those that occur between first-degree relatives—in other words, brother-sister or parent-child (Table 17.3). Marriage between first-degree relatives is forbidden, both on religious grounds and by legislation, in almost every culture. Incestuous relationships are associated with a very high risk of abnormality in offspring, with less than half the children of such unions being entirely healthy (Table 17.4).

Table 17.3 Genetic Relationship between Relatives and Risk of Abnormality in their Offspring

Genetic Relationship	Proportion of Shared Genes	Risk of Abnormality in Offspring (%)
First degree	1/2	50
Parent–child Brother–sister	1/2	50
Second degree	1/4	5–10
Uncle–niece Aunt–nephew Double first cousins	1/4	5–10
Third degree	1/8	3–5
First cousins	1/8	3–5

Table 17.4 Frequency of the Three Main Types of Abnormality in the Children of Incestuous Relationships

Abnormality	Frequency (%)
Intellectual impairment
Severe	25
Mild	35
Autosomal recessive disorder	10–15
Congenital malformation	10

Adoption and Genetic Disorders

The issue of adoption can arise in several situations relating to genetics. First, parents at high risk of having a child with a serious abnormality often express interest in adopting rather than running the risk of having an affected baby. In genetic terms, this is a perfectly reasonable option, although in practice the number of couples wishing to adopt usually far exceeds the number of babies and children available for adoption.

The physician with a knowledge of genetics can also be called on to try to determine whether a child who is being placed for adoption will develop a genetic disorder. For the offspring of consanguineous or incestuous matings, risks can be given as outlined previously (see Tables 17.3 and 17.4). Adoption societies sometimes also wish to place a child with a known family history of a particular hereditary disorder. This raises the difficult ethical dilemma of predictive testing in childhood for conditions showing onset in adult life (p. 365). Increasingly it is felt that such testing should not be undertaken unless this will be of direct medical benefit to the child. In practice, even when a child is actually affected by a genetic disorder, suitable adoptive parents can usually be found.

Concern about the possible misuse of genetic testing in neonates and young children who are up for adoption has prompted the American Society of Human Genetics and the American College of Medical Genetics to issue joint recommendations. These are based on the best interests of the child. They can be summarized as supporting genetic testing in such children only when the testing would be appropriate for all children of that age and when the tests are undertaken for disorders that manifest during childhood, for which preventive measures can be undertaken during childhood. The joint statement does not support testing for untreatable disorders of adult onset or for detecting predispositions to ‘physical, mental, or behavioral traits within the normal range’.

Disputed Paternity

This presents a difficult problem for which the help of a clinical geneticist is sometimes sought. Until recently paternity could never be proved with absolute certainty, although it could be disproved or excluded in two ways. If a child was found to possess a blood group or other polymorphism not present in either the mother or the putative father, then paternity could be confidently excluded. For example, if the mother and putative father both lacked blood group B, but this was present in the child, the putative father could be excluded. Similarly, if a child lacked a marker that the putative father would have had to transmit to all of his children, then once again paternity could be excluded. As an example, a putative father with blood group AB could not have a child with blood group O.

Early attempts to establish paternity were based on analysis of several different polymorphic systems, such as blood groups, isoenzymes and human leukocyte antigen haplotypes. The results of these studies can be consistent with paternity but cannot give absolute proof of it. Depending on the number of polymorphic systems analyzed and their frequencies in the general population, it is possible to calculate the relative probability that a particular male is the father compared with any male taken at random from the general population.

The limitations of these approaches have been overcome by the development of genetic fingerprinting using minisatellite repeat sequence probes (pp. 17, 69) and single nucleotide polymorphisms (SNPs) (p. 67). The pattern of DNA fragments generated by these probes, and SNP variants, is so highly polymorphic that the restriction map obtained is unique to each individual, with the exception of identical twins (Figure 17.4). If DNA from the child and the mother is analyzed, then the bands inherited from the biological father can be analyzed and compared with those present in DNA from the putative father(s). If these match, this gives an extremely high mathematical probability that the putative and biological fathers are the same individual.

FIGURE 17.4 Genetic fingerprint obtained using two minisatellite probes with DNA from a mother (M), father (F) and their twins (1 and 2). The twins have an identical set of bands and each band in the twins originates from one of the parents.

(Courtesy Dr. Raymond Dalgleish and Professor Sir Alec Jeffreys, University of Leicester. Reproduced from Young ID, Dalgleish R, Mackay EH, MacFadyen UM: Discordant expression of the G syndrome in monozygotic twins. Am J Med Genet 1988; 29:863–869, with permission from the American Journal of Medical Genetics.)

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Establishing the Diagnosis