Genetic Counseling and Risk Assessment in Medical Genetics
Medical genetics (sometimes called clinical genetics) is the branch of medicine concerned with the diagnosis and management of the medical, social, and psychological aspects of hereditary disease.
Genetic counseling, a critical aspect of clinical genetics, is the provision of appropriate information and advice about inherited conditions in order to allow informed reproductive choices to be made.
As in all other areas of medicine, it is essential to make a correct diagnosis and to provide appropriate treatment, which must include helping the affected person(s) and family members understand and come to terms with the nature and consequences of the disorder.
When a disorder is suspected of being heritable, however, there is an added dimension: the need to inform other family members of their risk and of the means available to them to modify these risks.
Just as the unique feature of genetic disease is its tendency to recur within families, the unique aspect of genetic counseling is its focus, not only on the original patient but also on members of the patient’s family, both present and future.
Genetic counseling is not limited to the provision of information and calculation of the risk for disease; rather, it is a process of exploration and communication.
The ability to define and address the complex psychosocial issues associated with a genetic disorder in a family is central to this practice.
Geneticists and genetic counselors can help with prevention and management, be a source of referral to subspecialists, and provide psychologically oriented counseling to help individuals adapt and adjust to the impact and implications of the disorder in the family.
Genetic counseling may be most effectively accomplished over time through periodic contact with the family as the medical or social issues become relevant to the lives of those involved.
The Process of Genetic Counseling
Common Indications for Genetic Counseling
Table X-1 lists some of the most common situations that lead people to pursue genetic counseling.
Often, the persons seeking genetic counseling (the consultands Opens in new window) are the parents of a child with a potential or known genetic condition, but the consultand may also be an adult who has a disorder of concern or a relative with such a disorder.
Genetic counseling is also an integral part of prenatal testing and of genetic testing and screening programs.
Table X-1 | Common Indications for Genetic Counseling
Previous child with multiple congenital anomalies, mental retardation, or an isolated birth defect such as neural tube defect or cleft lip and palate
Family history of a hereditary condition, such as cystic fibrosis, fragile X syndrome, or diabetes
Prenatal diagnosis for advanced maternal age or other indication
Consanguinity
Teratogen exposure, such as to occupational chemicals, medications, alcohol
Repeated pregnancy loss or infertility
Newly diagnosed abnormality or genetic condition
Before undertaking genetic testing and after receiving results, particularly in testing for susceptibility to late-onset disorders, such as cancer or neurological disese
As follow-up for a positive results of a newborn test, as with PKU; a heterozygote screening test, such as Tay-Sachs; or a positive first- or second-trimester maternal serum screen or abnormal ultrasound examination
Established standards of medical care require that providers of genetic services obtain a history that includes family and ethnic information, 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 of disease.
Although genetic counseling case management must be individualized for each patient’s needs and situation, a genetic approach can be summarized (Table X2).
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 consultanads, and their families.
This approach to counseling, referred to as nondirective counseling, has its origins in the setting of prenatal counseling and is firmly rooted in the guiding principle of respect for an individual couple’s right to make reproductive choices free of coercion.
Managing the Risk of 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 of recurrence of the particular genetic disorder in question.
Although prenatal diagnosis is one approach that can often be offered to families, it is by no means a universal solution to the risk of genetic problems in offspring.
There are many disorders for which prenatal diagnosis is not feasible, and for many parents, it is not an acceptable option even if its is available.
Other measures available for management of recurrence include:
Genetic laboratory tests (karyotyping, biochemical analysis, or DNA analysis) sometimes reassure couples with a family history of a genetic disorder that they themselves are not at increased risk of 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 to understand and to use the information gained through testing.
If the patients 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.
For parents who want a child or more children, adoption is possibility.
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 Opens in new window. In vitro fertilization with a donated egg may be appropriate if the mother has an autosomal dominant defect Opens in new window 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.
In some disorders, DNA analysis of embryos in the preimplantation stage can be carried out by the polymerase chain reaction of a single cell obtained from an early embryo generated by in vitro fertilization. For some parents, a decision not to implant an embryo found to be abnormal would be much more acceptable than abortion at a later stage.
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.
Genetic Counseling Providers
Increasingly, genetic counseling services are being provided by genetic counselors, qualified professionals trained in genetics and counseling, and nurse geneticists, serving as members of a heath care team with physicians.
Genetic counseling in the United States and Canada is a self-regulating health profession with its own board for accreditation of training programs and certification of practitioners. 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 makes with clinical genetic services, provides genetic counseling directly to consultands, helps patients and families deal with the many psychological and social issues that arise during a genetic counseling, and continues in a supportive role and as a source of information after the clinical investigation and formal counseling have been completed.
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 good communication skills.
Referral to family and patient support groups is often made by counselors in managing a patient and family with a genetic disorder or birth defect. 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 with others facing the same problem, to learn how to deal with the day-to-day problems caused by the disorder, to hear of new development in therapy for 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.
In the United States, the Genetic Alliance, a broad coalition of many patient advocacy and family support groups, serves to coordinate the activities of many individual groups.
Table X-2 | Genetic Counseling Case Management
Collection of information
Family history (questionnaire) Medical history Tests or additional assessments
Assessment
Physical examination Laboratory and radiological testing Validation or establishment of diagnosis—if possible
Counseling
Nature and consequence of disorder
Recurrence risk
Availability of further or future testing
Decision-making
Referral to other specialists, health agencies, support groups
Continuing clinical assessment, especially if no diagnosis
Psychosocial support
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 Opens in new window of the particular family being counseled.
The family member whose risk of a genetic disorder is to be determined is usually a relative of a proband Opens in new window, such as a sib of an affected child or a living or future child of an affected adult.
In some families, especially for some autosomal dominant Opens in new window 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.
Under these circumstances, mendelian risk estimates can sometimes be modified by means of applying conditional probability Opens in new window to the pedigree, which takes into account information about the family that may increase or decrease the underlying mendelian risk.
In contrast to single-gene disorders, the underlying mechanisms of inheritance for most chromosomal disorders and complex traits are unknown, and estimates of recurrence risk are based on previous experience.
This approach to risk assessment is valuable if there are good 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.
Risk Estimation When Genotypes Are Fully Known by Use of Mendel’s Laws
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, and one is interested in the chance of the couple’s having another affected child, the risk (probability) is one in four with each pregnancy that the child will inherit two mutant alleles and inherit the disease.
Even if the couple were to have six unaffected children subsequent to the affected child, the risk in the eighth, ninth, or tenth pregnancy is still one in four for each pregnancy (assuming there is no misattributed paternity for the first affected child).
Risk Estimation by Use of Conditional Probability When Alternative Genotypes Are Possible
In contrast to the simple case described, situations arise in which the genotypes of the relevant individuals in the family are not definitely known; the risk of recurrence will be very different, depending on whether or not the cosultand 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) Opens in new window might have an affected child depends on the chance that her husband by her second marriage is a carrier.
The risk of the partner’s being a carrier depends on his ethnic background. For the general white population, this chance is 1/22. Therefore, the chance that a known carrier and her unrelated partner would have an affected first child is the product of these probabilities, or 1/22 x 1/4 = 1/88 (about 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 1/4. If the husband were not a carrier, then the chance of having an affected child is 0.
Suppose, however, that one cannot test his carrier status directly. A carrier risk of 1/22 is the best estimate one can make for individuals of his ethnic background and no family history of CF, but in fact, 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 (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, it would seem reasonable, intuitively, that the husband’s chance of being a carrier should be less than the 1/22 risk that the childless male partner 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’ theorem on probability published in 1973), 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. The chance that the second husband is a carrier is actually 1/119 and the chance that this couple would have a child with CF is 1/476.
