Hereditary diseases

Classification by type of genetic defect

Etiologically, congenital pathologies and developmental anomalies are divided into three major categories:

1. Genetic (hereditary) — caused by mutations at the level of individual genes or the structure/number of chromosomes.
2. Exogenous — formed under the action of damaging teratogenic agents on the embryo (e.g., rubella virus or alcohol).
3. Multifactorial — the result of a combination of hereditary predisposition and adverse external triggers.

Hereditary forms themselves are classified by the level of genome lesion: monogenic defects, polygenic combinations, and chromosomal diseases.

Monogenic nuclear genome pathologies

Monogenic diseases obey Mendel's laws of segregation and are divided depending on the localization of the gene and the nature of its manifestation:

• Autosomal dominant (up to 15% of cases): the pathology manifests in heterozygotes. Examples: Huntington's disease (locus on chromosome 4), Marfan syndrome, Noonan syndrome (PTPN11), Holt–Oram syndrome (TBX5), familial hypercholesterolemia, polydactyly.
• Autosomal recessive (75–85% of cases): manifest in homozygotes, parents are usually phenotypically healthy, and the pedigree demonstrates "horizontal" transmission. The risk increases sharply in consanguineous marriages. Examples: phenylketonuria, cystic fibrosis (chromosome 7), adrenogenital syndrome, alkaptonuria, Wilson's disease (chromosome 13), Meckel–Gruber syndrome (MKS1).
• X-linked recessive: predominantly affect males, with mothers acting as asymptomatic or mildly symptomatic carriers. Examples: hemophilia A (Xq28 locus), Duchenne–Becker muscular dystrophy (Xq21), Hunter syndrome.
• X-linked dominant: twice as common in females, but more severe in males due to hemizygosity (vitamin D-resistant rickets, Charcot–Marie–Tooth disease).
• Y-linked (holandric): transmitted strictly from father to sons (azoospermia, hypertrichosis of the pinnae).

Chromosomal disorders and mitochondrial genome

In chromosomal diseases, the number or structure of chromosomes is disrupted. A distinction is made between complete forms (the anomaly arises in gametes and affects all cells) and mosaic forms (the breakdown occurs at early stages of somatic cell cleavage).

Mitochondrial diseases are associated with defects in the respiratory chain and oxidative phosphorylation. If the mutation is localized in the mitochondrial circular mtDNA itself, the disease is transmitted exclusively through the maternal line. If the defect affects nuclear genes encoding mitochondrial proteins, inheritance follows classical Mendelian laws.

Multifactorial pathologies and oncogenetics

In polygenic multifactorial diseases, the clinical picture is formed by the cumulative effect of multiple genes and provoking environmental factors; they do not obey Mendel's laws. This group includes isolated congenital heart defects and neural tube defects.

In oncology, to assess tumor transformation, risk, and select therapy, molecular markers are studied:

• cell cycle and proliferation proteins (Ki-67, p53);
• apoptosis regulators (Bcl-2, survivin);
• receptors and adhesion factors (HER-2, E-cadherin);
• microsatellite instability markers (MMR) used for Lynch syndrome screening.

Class and exam questions

What else to study on this topic

• T. Morgan's chromosomal theory of linkage and crossing over
• Ontophylogenetic mechanisms of congenital heart defects (heterochrony and recapitulation)
• Molecular tumor analysis methods (FISH hybridization, blotting, flow cytometry)
• Genetic heterogeneity of hereditary traits using hereditary deafness as an example
• Monogenic multiple malformation syndromes (Ellis–van Creveld, Smith–Lemli–Opitz, Aarskog, Lenz syndromes)

Other topics in the "Additional Topics" section

Prepared by WhiteCoat Pro faculty in accordance with the medical school curriculum. For educational purposes only.