Genetic studies: indications, methods

In recent years, an increase in the share of hereditary diseases in the overall structure of diseases has been observed. In this regard, the role of genetic research in practical medicine is increasing. Without knowledge of medical genetics, it is impossible to effectively diagnose, treat and prevent hereditary and congenital diseases.

Hereditary predisposition is probably inherent in almost all diseases, but its degree varies considerably. If we consider the role of hereditary factors in the occurrence of various diseases, we can distinguish the following groups.

• Diseases whose origin is entirely determined by genetic factors (the impact of a pathological gene); this group includes monogenic diseases, the inheritance of which is subject to the basic rules of Mendel's laws (Mendelian diseases), and the impact of the external environment can only affect the intensity of certain manifestations of the pathological process (its symptoms).
• Diseases, the occurrence of which is determined mainly by the influence of the external environment (infections, injuries, etc.); heredity can only influence some quantitative characteristics of the body's reaction, determine the features of the course of the pathological process.
• Diseases in which heredity is a causal factor, but for its manifestation certain environmental influences are necessary, their inheritance does not obey Mendel's laws (non-Mendelian diseases); they are called multifactorial.

Hereditary diseases

The development of each individual is the result of the interaction of genetic and environmental factors. The set of human genes is established during fertilization and then, together with environmental factors, determines the characteristics of development. The set of genes of an organism is called the genome. The genome as a whole is quite stable, but under the influence of changing environmental conditions, changes - mutations - can occur in it.

The basic units of heredity are genes (sections of the DNA molecule). The mechanism of transmission of hereditary information is based on the ability of DNA to self-duplicate (replicate). DNA contains a genetic code (a system of recording information about the location of amino acids in proteins using the sequence of nucleotides in DNA and messenger RNA), which determines the development and metabolism of cells. Genes are located in chromosomes, structural elements of the cell nucleus containing DNA. The place occupied by a gene is called a locus. Monogenic diseases are monolocus, polygenic diseases (multifactorial) are multilocus.

Chromosomes (the rod-shaped structures in the nuclei of cells visible under a light microscope) consist of many thousands of genes. In humans, each somatic, or non-sex, cell contains 46 chromosomes, represented by 23 pairs. One of the pairs, the sex chromosomes (X and Y), determines the sex of the individual. In the nuclei of somatic cells, women have two X chromosomes, while men have one X and one Y chromosome. The sex chromosomes of men are heterologous: the X chromosome is larger and contains many genes responsible for both sex determination and other characteristics of the organism; the Y chromosome is small, has a shape different from the X chromosome, and carries mainly genes that determine the male sex. Cells contain 22 pairs of autosomes. Human autosomal chromosomes are divided into 7 groups: A (1st, 2nd, 3rd pairs of chromosomes), B (4th, 5th pairs), C (6th, 7th, 8th, 9th, 10th, 11th, 12th pairs, as well as chromosome X, similar in size to chromosomes 6 and 7), D (13th, 14th, 15th pairs), E (16th, 17th, 18th pairs), F (19th, 20th pairs), G (21st, 22nd pairs and chromosome Y).

Genes are arranged linearly along chromosomes, with each gene occupying a strictly defined place (locus). Genes that occupy homologous loci are called allelic. Each person has two alleles of the same gene: one on each chromosome of each pair, with the exception of most genes on chromosomes X and Y in males. When homologous regions of a chromosome contain identical alleles, we speak of homozygosity; when they contain different alleles of the same gene, we speak of heterozygosity for a given gene. If a gene (allele) exhibits its effect when present on only one chromosome, it is called dominant. A recessive gene exhibits its effect only if it is present in both members of a chromosome pair (or on the single X chromosome in males or in females with the X0 genotype). A gene (and the corresponding trait) is called X-linked if it is localized on chromosome X. All other genes are called autosomal.

A distinction is made between dominant and recessive inheritance. In dominant inheritance, a trait is manifested both in the homozygous and heterozygous states. In recessive inheritance, phenotypic (a set of external and internal traits of an organism) manifestations are observed only in the homozygous state, while they are absent in heterozygosity. A sex-linked dominant or recessive inheritance is also possible; in this way, traits associated with genes localized in sex chromosomes are inherited.

Dominantly inherited diseases usually affect several generations of a single family. In recessive inheritance, latent heterozygous carriage of a mutant gene may exist in a family for a long time, due to which sick children may be born to healthy parents or even in families in which the disease has been absent for several generations.

Gene mutations underlie hereditary diseases. Understanding mutations is impossible without a modern understanding of the term "genome". Currently, the genome is considered a multigenome symbiotic structure consisting of obligatory and facultative elements. The basis of obligatory elements are structural loci (genes), the number and location of which in the genome are fairly constant. Structural genes account for approximately 10-15% of the genome. The concept of "gene" includes the transcribed region: exons (the actual coding region) and introns (a non-coding region separating exons); and flanking sequences - the leader, preceding the beginning of the gene, and the tail untranslated region. Facultative elements (85-90% of the entire genome) are DNA that does not carry information about the amino acid sequence of proteins and is not strictly obligatory. This DNA can participate in the regulation of gene expression, perform structural functions, increase the accuracy of homologous pairing and recombination, and promote successful DNA replication. The participation of facultative elements in the hereditary transmission of traits and the formation of mutational variability has now been proven. Such a complex genome structure determines the diversity of gene mutations.

In the broadest sense, a mutation is a stable, inherited change in DNA. Mutations may be accompanied by changes in the structure of chromosomes that are visible under a microscope: deletion - loss of a section of a chromosome; duplication - doubling of a section of a chromosome, insertion (inversion) - a break in a section of a chromosome, its rotation by 180° and attachment to the site of the break; translocation - breaking off a section of one chromosome and attaching it to another. Such mutations have the greatest damaging effect. In other cases, mutations may consist of the replacement of one of the purine or pyrimidine nucleotides of a single gene (point mutations). Such mutations include: missense mutations (mutations with a change in meaning) - replacement of nucleotides in codons with phenotypic manifestations; nonsense mutations (senseless) - replacement of nucleotides that form termination codons, as a result of which synthesis of the protein encoded by the gene is prematurely terminated; splicing mutations - substitutions of nucleotides at the junction of exons and introns, which leads to the synthesis of elongated protein molecules.

A new class of mutations has been identified relatively recently - dynamic mutations or expansion mutations associated with instability of the number of trinucleotide repeats in functionally significant parts of genes. Many trinucleotide repeats localized in transcribed or regulatory regions of genes are characterized by a high level of population variability, within which phenotypic disorders are not observed (i.e., the disease does not develop). The disease develops only when the number of repeats in these sites exceeds a certain critical level. Such mutations are not inherited in accordance with Mendel's law.

Thus, hereditary diseases are diseases caused by damage to the cell genome, which can affect the entire genome, individual chromosomes and cause chromosomal diseases, or affect individual genes and be the cause of gene diseases.

All hereditary diseases are usually divided into three large groups:

• monogenic;
• polygenic, or multifactorial, in which mutations of several genes and non-genetic factors interact;
• chromosomal abnormalities, or anomalies in the structure or number of chromosomes.

Diseases belonging to the first two groups are often called genetic, and those belonging to the third group are called chromosomal diseases.

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Classification of hereditary diseases

Chromosomal	Monogenic	Multifactorial (polygenic)
Anomalies in the number of sex chromosomes: - Shereshevsky-Turner syndrome; - Klinefelter syndrome; - trisomy X syndrome; - syndrome 47, XYY Autosomes: - Down's syndrome; - Edwards syndrome; - Patau syndrome; - partial trisomy 22 Structural abnormalities of chromosomes: Cri du chat syndrome; 4p deletion syndrome; Neighboring gene microdeletion syndromes	Autosomal dominant: Marfan syndrome; von Willebrand disease; Minkowski-Shoffar anemia and others Autosomal recessive: - phenylketonuria; - galactosemia; - cystic fibrosis, etc. X-linked recessive: Hemophilia A and B; Duchenne myopathy; And others. X-linked dominant: - vitamin D-resistant rickets; - brown coloration Tooth enamel, etc.	CNS: some forms of epilepsy, schizophrenia, etc. Cardiovascular system: rheumatism, hypertension, atherosclerosis, etc. Skin: atopic dermatitis, psoriasis, etc. Respiratory system: bronchial asthma, allergic alveolitis, etc. Urinary system: urolithiasis, enuresis, etc. Digestive system: peptic ulcer, nonspecific ulcerative colitis, etc.

Chromosomal diseases can be caused by quantitative chromosome anomalies (genomic mutations), as well as structural chromosome anomalies (chromosomal aberrations). Clinically, almost all chromosomal diseases manifest themselves as intellectual disabilities and multiple congenital defects, often incompatible with life.

Monogenic diseases develop as a result of damage to individual genes. Monogenic diseases include most hereditary metabolic diseases (phenylketonuria, galactosemia, mucopolysaccharidoses, cystic fibrosis, adrenogenital syndrome, glycogenoses, etc.). Monogenic diseases are inherited according to Mendel's laws and, according to the type of inheritance, can be divided into autosomal dominant, autosomal recessive, and X-linked.

Multifactorial diseases are polygenic, and their development requires the influence of certain environmental factors. The general signs of multifactorial diseases are as follows.

• High frequency in the population.
• Pronounced clinical polymorphism.
• Similarity of clinical manifestations in the proband and close relatives.
• Age and gender differences.
• Earlier onset and some increase in clinical manifestations in descending generations.
• Variable therapeutic efficacy of drugs.
• Similarity of clinical and other manifestations of the disease in close relatives and the proband (the heritability coefficient for multifactorial diseases exceeds 50-60%).
• Inconsistency of inheritance patterns with Mendel's laws.

For clinical practice, it is important to understand the essence of the term "congenital malformations", which can be single or multiple, hereditary or sporadic. Hereditary diseases do not include those congenital diseases that occur during critical periods of embryogenesis under the influence of unfavorable environmental factors (physical, chemical, biological, etc.) and are not inherited. An example of such a pathology can be congenital heart defects, which are often caused by pathological effects during the period of heart formation (first trimester of pregnancy), for example, a viral infection tropic to the tissues of the developing heart; fetal alcohol syndrome, developmental anomalies of the limbs, auricles, kidneys, digestive tract, etc. In such cases, genetic factors form only a hereditary predisposition or increased susceptibility to the effects of certain environmental factors. According to WHO, developmental anomalies are present in 2.5% of all newborns; 1.5% of them are caused by the action of unfavorable exogenous factors during pregnancy, the rest are mainly of genetic nature. The distinction between hereditary and congenital diseases that are not inherited is of great practical importance for predicting offspring in a given family.

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Methods of diagnostics of hereditary diseases

Currently, practical medicine has a whole arsenal of diagnostic methods that allow hereditary diseases to be detected with a certain probability. The diagnostic sensitivity and specificity of these methods vary - some allow only to assume the presence of a disease, while others with great accuracy detect mutations that underlie the disease or determine the characteristics of its course.

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Cytogenetic methods

Cytogenetic research methods are used to diagnose chromosomal diseases. They include:

• sex chromatin studies - determination of X- and Y-chromatin;
• karyotyping (karyotype is the set of chromosomes of a cell) - determination of the number and structure of chromosomes for the purpose of diagnosing chromosomal diseases (genomic mutations and chromosomal aberrations).

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