Medical Genetics - V. M. Zaporozhan 2005

Monogenic Disorders
Genetic Counseling

When determining the probability of having an affected child, the following factors are taken into account:

— the mode of Inheritance of the disease;

— the parents' genotype;

— the penetrance of the Gene (for dominantly inherited conditions);

— the disease frequency in the population (for recessive disorders).

If the parents' genotype is known, Mendel's Laws are used to calculate the risk (Table 6.12).

In other cases, the calculation is more complex, based on the laws of probability, and takes into account the prevalence of the disease in the population. For example, cystic fibrosis is inherited as an autosomal recessive trait. The probability of having a child with cystic fibrosis from heterozygous parents is 1/4, or 25% (Aa × Aa). For any healthy couple, the probability of having a child with cystic fibrosis is determined by the carrier frequency of the gene in the population (1/20). The probability that both parents are heterozygous is 1/20 × 1/20 = 1/400; the probability of having an affected child in this case will be 1/4. The combined probability for a couple with no family history of cystic fibrosis will be 1/20 × 1/20 × 1/4 = 1/1600 (population risk).

Table 6.12. Probability of having an affected child depending on the mode of inheritance and parents' genotype

Table 6.13. Diagnostic Methods for heterozygote carrier status in specific disorders

Identification of heterozygotes in MEDICAL GENETIC COUNSELING. For certain disorders, heterozygous carriers can be identified with a high degree of probability. It should be borne in mind that every individual is a heterozygous carrier of at least 10 recessive pathological genes, including 4–5 lethal ones. Heterozygote detection is advisable when There is a high risk of carrier status:

1) in sisters of boys with an X-linked recessive disorder (Duchenne muscular dystrophy, hemophilia, Lesch–Nyhan syndrome);

2) in healthy sibs within families having affected members with an autosomal recessive disorder;

3) among population groups with a relatively high frequency of a recessive pathological gene in the population (Tay–Sachs disease in Ashkenazi Jews, sickle cell anemia in certain regions of Africa, and beta-thalassemia in Mediterranean populations).

There are several ways to detect heterozygous carrier status:

1. Clinical symptomatology in heterozygotes. Sometimes carriers of certain pathological genes exhibit minimal clinical manifestations of the disease that are only revealed through detailed examination. This is observed in some X-linked disorders in heterozygous females due to random X-chromosome inactivation carrying the normal gene. For instance, female carriers of the fragile X syndrome gene often have slightly reduced intelligence, while carriers of anhidrotic ectodermal Dysplasia show patches of skin lacking Sweat Glands. Female heterozygous carriers of hemophilia frequently form hematomas, though the same can also be observed in normal women.

2. Biochemical diagnostics. In certain disorders, biochemical alterations result from the direct action of genes. Enzyme activity in carriers occupies an intermediate position compared to healthy individuals and patients

(reduced by approximately half relative to normal values).

3. Molecular Genetic Methods are the most precise.

Methods for diagnosing heterozygous carrier status in specific disorders are presented in Table 6.13.