Basics of Medical Genetics - Buzhiyevska T.I. 2001

Hereditary Diseases

Hereditary diseases are disorders associated with damage to genetic structures. The condition may be inherited from parents (segregant proband) or arise de novo in an individual As a result of a mutation (mutant proband). Both types can be transmitted across generations (inheritable diseases) or remain non-inheritable due to Infertility in the affected individual.

Based on The Nature and extent of genetic damage, hereditary diseases can be classified as: 1) genomic, i.e., associated with an abnormal chromosome number in all Cells or in a specific fraction of Cells and Tissues (mosaicism); 2) chromosomal, characterized by unbalanced structural chromosome aberrations such as deletions (loss of a chromosomal segment), duplications (doubling of a segment), translocations (transfer of a chromosomal segment of varying size to an inappropriate site or chromosome), and other abnormalities that alter Gene localization and dosage; 3) monogenic, resulting from a mutation in a single gene encoding a specific trait. Among Monogenic Disorders, based on their mode of inheritance, a distinction is made between autosomal and sex-linked conditions, where the affected genes reside in autosomes or sex Chromosomes, respectively.

Monogenic hereditary diseases are further subdivided into dominantly and recessively inherited. In a dominant syndrome, the mutant gene manifests not only in the homozygous but also in the heterozygous state. Autosomal dominant (AD) syndromes are frequently lethal in homozygotes (if both alleles are dominant and defective). The pathology is transmitted vertically from affected parents to their children (vertical pedigree transmission), and its severity depends on the penetrance and expressivity of the affected gene (Fig. 8).

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Fig. 8. Pedigree of proband K. Diagnosis: Rubinstein-Taybi

syndrome. AD inheritance pattern; ◩, ◐ - incomplete expressivity of the syndrome

X-linked dominant (XD) disorders manifest in both females and males; the clinical course is typically more severe in males due to their hemizygous state.

Autosomal recessive (AR) inherited diseases affect children born to healthy parents who are heterozygous carriers of the mutant gene, as a result of combinatorial Variability. According to Mendelian laws, 25% of children born to heterozygous parents may be homozygous for the mutant recessive allele and thus affected. The pathology exhibits horizontal transmission in the pedigree. All offspring of affected individuals from non-consanguineous marriages will be carriers of this gene while remaining clinically healthy (see Fig. 7).

X-linked recessive (XR) disorders affect hemizygous males, being transmitted from a grandfather through a mother (carrying the mutant allele) to a grandson.

Girls are rarely affected, requiring an X chromosome carrying the recessive mutant gene from both mother and father, which typically occurs in consanguineous marriages.

Fig. 9. Outcomes of genotype-environment interactions. Acquired and hereditary human diseases

Y-linked disorders are transmitted exclusively from father to son and are exceptionally rare.

AD pathologies are mostly lethal in the homozygous state, may stem from de novo Mutations, and exhibit mutational pressure.

AR and XR diseases predominantly determine the segregational load and result from combinatorial variability.

Multifactorial pathologies result from combinatorial variability, wherein children inherit a complex of mutant genes from both parents sufficient to trigger the disease. Alongside numerous disease-causing genes, environmental factors play a major role in the Etiology AND Pathogenesis of these conditions.

There are also sex-limited disorders, which should be distinguished from sex-linked ones. In this case, the mutant alleles reside in an autosome (rather than a sex chromosome), yet only individuals of one sex are affected. For instance, hypospadias develops exclusively in boys, whereas impaired Lactation occurs solely in females.

In this chapter, the author seeks to emphasize The Role of heredity in The Development of all human diseases, rather than isolating solely hereditary and thus exceedingly rare pathologies. Consequently, chromosomal and monogenic syndromes are not segregated from other pediatric disorders. Contrary to traditional presentation, the material is structured to demonstrate that hereditary pathologies with specific etiopathogenetic features exist across diseases of all Organs and systems (Fig. 9). Only illustrative Examples of such pathologies are provided within each disease category, given that approximately 4,000 monogenic syndromes alone have been documented across various monographs, atlases, and reference guides.