Genetic counseling provides information concerning the risks of occurrence of genetic disorders and the reproductive options available to prospective parents. Since genetic factors play an etiologic role in many different diseases, genetic counseling has become an important component of patient management. If there is a significant risk that a given disease will recur in future children, physicians should provide or arrange for genetic counseling even if the patient or parents do not specifically request such advice. Genetic counseling not only gives factual information but also adapts the communication process to the needs of the individual patient and his family. Alleviation of guilt and explanations regarding the nature and severity of the disease under study are always required. The natural history of the disease, including its variability from patient to patient as well as the potential personal, medical, and social burden, must be conveyed.
Diagnosis of Genetic counseling .
Accurate diagnosis is a prerequisite for genetic counseling. Similar-appearing diseases may be inherited by different modes of transmission (heterogeneity) or may not be genetic at all. Accurate diagnosis requires a carefully obtained family history which is best denoted by conventional pedigree symbols. Information about relatives regarding age, onset of a given disease, health status, and cause of death is obtained. Knowledge of the ethnic origin of the family may be helpful in considering certain genetic diseases; Tay-Sachs disease is common in Jews of European origin, and cystic fibrosis is rare in blacks. Advanced maternal age is a predisposing factor to chromosomal errors such as Down’s and Kline-felter’s syndromes.
Advanced paternal age may be found when new mutations for autosomal dominant diseases such as Marfan’s disease or achondroplasia are suspected. Historic data on the immediate family are more accurate than information regarding more remote relatives. Occasionally, physicians’ and hospital records have to be obtained for documentation of suspected diseases. Genetic diseases manifesting anomalies of stature or a characteristic physiognomy can sometimes be recognized in photographs of family members. If the parents are related, or if both the father’s and mother’s ancestors originated from a restricted rural area, au-tosomal recessive inheritance should be considered as the possible cause for an obscure disease.
The mode of inheritance together with the clinical and laboratory findings of a given patient may be helpful in defining various subtypes of clinically similar-appearing genetic disorders such as Hurler’s (autosomal recessive) and Hunter’s (X-linked recessive) disease, or Marfan’s disease (autosomal dominant! and homocystinuria (autosomal recessive). Diagnosis and appropriate counseling for the majority of genetic diseases require knowledge of the clinical and genetic features of the disease rather than special “genetic tests.” Suitable cytogenetic and enzymatic tests should be available in the investigation of some conditions. However, because chromosomal aberrations usually are sporadic events and do not run in families, chromosomal analyses are not helpful for counseling in most genetic diseases.
If a disease is transmitted by a men-delian or monogenic pattern, recurrence risks can be well defined. Lack of clinical manifestation (diminished penetrance) or variable expression is particularly frequent in autosomal dominant disorders. In addition to the information that a given gene will be transmitted with a certain probability, the actual recurrence risk of the clinical symptomatology and the risk for severe manifestations associated with that gene must be communicated to the patient. As an example, only 10 to 20 per cent of the gene carriers for Waardenberg’s syndrome (autosomal dominant) are deaf. Deafness, rather than the pigmentary and eye anomalies associated with that condition, is disabling, and the problems and recurrence risks of deafness must be stressed during genetic counseling. Some genetic diseases transmitted by an autosomal dominant mechanism, such as polycystic kidneys and Huntingtons chorea, only express themselves clinically in the middle-aged. The risk for unaffected offspring of patients, which is 50 per cent at birth, becomes progressively less as a person remains unaffected beyond the age at which these diseases first manifest.
Curve plotting the age of onset can be used to quant itate these risks. McKusick’s catalogue of mendelian disorders gives helpful short descriptions and literature citations for the known mendelian genetic diseases.
Since in polygenic conditions the number of genes and their relative contributions are unknown, genetic theory does not allow prediction of genetic risks, and so-called empiric risk figures must be relied on for counseling. Similarly, the transmission of viable chromosomal aberrations, such as translocations, does not usually follow mendelian principles, and counseling must also be based on empirically derived risk figures. Empiric risk figures are obtained from observing the frequency of recurrence of the disease in many affected families. Fortunately, recurrence risks for polygenic diseases are rarely higher than 5 per cent. Because empiric risks are derived from genetically heterogeneous families, they do not have the scientific precision of recurrence risks for mendelian disease.
Risk assessment requires recognition of the occasional monogenic variant among the broad category of a common disease by careful consideration of the family history and possible differentiating clinical and laboratory features. For instance, autosomal dominant familial hypercholesterolemia is found in 5 per cent of patients who have a myocardial infarction at or below age 60.
Absolute recurrence risks are more meaningful to a family than relative risks. A 1000-fold increase in recurrence risk for a certain disease in a family appears frightening. However, for a condition which occurs in 1 of 100,000 births, a 1000-fold increase means that the absolute or actual risk of recurrence is only 1 per cent —a rather low risk. In mendelian diseases the recurrence risk is fixed (e.g., 25 per cent for autosomal recessive disease I, whether several or no affected children preceded. In polygenic diseases, if several sibs are affected in a given family, more disease-producing genes are operative in that sib-ship. and the risk for future offspring becomes higher.
The meaning of genetic risks must be conveyed in terms understandable to patients. Qualitative terms such as “high” for 50 per cent risks, ’’substantial” for 25 per cent risks, and “low” for risks of 5 per cent or less may be helpful for optimal communication. The probability that approximately 3 per cent of all children of normal couples will develop serious birth defects, genetic disease, or mental retardation should be communicated as a measure against which the additional risks can be gauged.
Once the significance of the recurrence risk and the contribution of heredity to the disorder have been considered, reproductive alternatives which are meaningful within the social, emotional, and religious framework of the particular family must be discussed. Occasionally, it may be appropriate to give firm and directive advice. More generally, genetic counseling should be nondirective and should provide the necessary information to allow a couple to make their own decisions regarding future reproduction. A genetic counselor should not force his values on those who seek his advice. On the other hand, a scientifically cool and aloof stance is not sufficient, and a sympathetic discussion of the many problems faced by the family is required.
Heterozygote Detection And Genetic Counseling.
Heterozygote detection is particularly important in sisters of males affected with X-linked recessive diseases such as hemophilia and Du-chenne type muscular dystrophy, because regardless of their husbands genetic constitution, there is a 50 per cent risk that the sons of female carriers will be affected. In contrast, autosomal recessive disease becomes evident only when both parents are carriers, and a heterozygote sib of an affected patient must mate with another heterozygote for the disease to occur. The chance that an unrelated mate will be a carrier is usually quite low. Specialized laboratory tests for carrier detection (such as creatine phosphokinase enzyme assays in Duchenne muscular dystrophy) may lit* helpful hut must be carefully standardized on normal subjects and known het ero/yuotes before applying them for individual carrier identification Detection of carriers is relatively simple in the hemoglobinopathies, and an increasing number of hclerocygote states for various enzyme deficiencies such as Tay-Sachs disease can be recognized.
Fragmentary data suggest that couples who sought genetic counseling have had fewer children if the genetic risk was more than 10 per cent. If a couple decides that the risks for further reproduction are too high, several options besides contraception sometimes must be discussed. Adoption is becoming less practicable because fewer babies are available. Sterilization of either husband or wife may be considered, but it must be emphasized that this is an irreversible procedure. Thus sterilization is undesirable for prevention of autosomal recessive conditions, because remarriage after possible divorce or death could eliminate the genetic risks almost entirely. Artificial insemination by a donor other than the husband may he acceptable to occasional couples to prevent autosomal recessive disease or autosomal dominant disease contributed by the husband.
Intrauterine diagnosis provides a definite diagnosis and replaces statistical likelihood with certainty. Parents may select abortion if the fetus is affected and. with monitoring of future pregnancies by amniocentesis, may be assured unaffected children.
Detection of Genetic Disease in Relatives.
Optimal genetic counseling in some diseases includes the testing of relatives at risk In some conditions the detection of latent disease in sibs and other relatives, if followed by suitable therapy, may be lifesaving. A sib of a patient with Wilson’* disease ‘autosomal recessive• has a 25 per cent chance of being affected but may be boo young to exhibit overt symptoms. Sibs of patients with hereditary polyposis of the colon inutoMimal dominant) have a 50 per cent chance of being affected and therefore carry the certain risk of developing malignant transformation of one of the many polyps In general, vigorous attempts should be made to examine relatives, using appropriate tests, when a genetic condition causes serious preventable or treatable disease. Possible carriers for serious X-linked diseases ‘such as hemophilia) and for chromosomal carrier status isuch as Down’s syndrome associated.with translocation should be sought in families for prevention by intrauterine diagnosis and possible abortion.
Genetic counseling has usually been retrospective and has followed the advent of a sick child or relative. In prospective counseling, advice is given before a sick person is born Such an approach is possible for common autosomal recessive diseases such as sickle cell anemia, thalassemia major, and Tay-Sachs disease in populations with high frequencies of these genes. Eight per cent of the American black population are carriers of the sickling gene, and 4 per cent of the American Jewish population of European extraction are carriers of the Tay-Sachs gene. Mass screening for heterozygote detection followed by suitable genetic counseling has been proposed.
Identification of the sickle cell trait before reproduction permits the prevention of sickle cell anemia if carriers refrain from mating with each other or if those already married have no children Such programs raise many ethical and social problems, and it is doubtful whether mating and reproductive choices which are logical from the points of view of medicine, genetics, and public health would actually he made Unfortunately, many sickling screening programs have been established without adequate counseling Often the mistaken notion has been promoted that the sickle cell trait represents a mild form of sickle cell disease. Needless anxiety and occupational discrimination against sickle cell trail carriers have resulted. Screening programs for Tay-Sachs disease have been more successful because intrauterine detection of this condition is possible.