Medical Genetics - V. M. Zaporozhan 2005

Clinical-genealogical method
Characteristics of pedigrees with various inheritance patterns
Autosomal dominant inheritance pattern

With this type of inheritance, a single mutant allele (heterozygous state) located on one of the autosomes is sufficient for the disease to develop. The mutant allele is designated as A, and the normal one as a. Affected individuals are usually heterozygous (Aa). Homozygotes (AA)—those with two pathological alleles—are mostly unviable. A classic pedigree with an autosomal dominant mode of inheritance (Fig. 4.3) is characterized by the following features:

1. A high frequency of affected individuals in the pedigree.

2. The trait is transmitted from one of the parents to the offspring without skipping generations (so-called "vertical" transmission of the disease). Typically, an affected child has one affected parent.

3. The ratio of affected males to females is approximately equal.

4. Affected males and females transmit the disease to children of both sexes with equal probability.

5. The ratio of affected to healthy offspring from an affected parent is close to 50%, meaning that in most cases, if one parent is affected (Aa) and the other is healthy, the probability of having an affected child is 50%.

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6. Healthy parents have only healthy children.

Fig. 4.3. Pedigree for autosomal dominant inheritance of a trait

Pedigrees associated with a dominant mode of inheritance may deviate from the classic pattern in the following cases:

1. A child with a dominant disorder may be born to healthy parents. This is due to a de novo germline mutation in one of the parents (most frequently the father) or a somatic mutation in the embryo. The birth of two or more affected children may result from Gonadal Mosaicism in healthy parents.

2. Dominant traits are characterized by incomplete penetrance and variable expressivity of the dominant genes. Penetrance refers to the frequency with which a dominant Gene manifests phenotypically. It is defined as the percentage of affected individuals among all carriers of the dominant allele in a population. In cases of incomplete penetrance, the disease-causing gene may be inherited yet fail to manifest phenotypically.

METABOLISM/2.html">THE CONCEPT OF expressivity is analogous to the severity of a disease. Variable expressivity reflects differences in the degree of phenotypic manifestation of a trait.

Fig. 4.4. Pedigree for Autosomal Recessive Inheritance of a trait

In the presence of incomplete penetrance and variable expressivity, skipped generations may appear in a pedigree with a dominantly inherited disorder.

3. Certain diseases do not manifest at birth but rather at a later age (e.g., adult-onset Polycystic Kidney Disease, Huntington's disease, hereditary Alzheimer's disease). In such instances, at the time of pedigree construction, a carrier of the dominant gene may still be healthy, making reliable Genetic Counseling impossible without The Use of DNA diagnostic Methods. Occasionally, heterozygous gene carriers die prior to the clinical onset of the disease from causes unrelated to the hereditary disorder.

4. If the mutation affects sex-limited traits (such as uterine anomalies), only individuals of one sex will be affected. The severity of the disease course may also be determined by the sex of the transmitting parent or the sex of the affected individual.