Genetic studies: indications, methods

In recent years, an increase in the proportion of hereditary diseases in the overall structure of diseases has been traced. 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 likely 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 of them.

• Diseases, the origin of which is completely determined by genetic factors (exposure to a pathological gene); This group includes monogenic diseases, the inheritance of which is subject to the basic rules of Mendel's laws (mendelirovannye disease), and the impact of the external environment can affect only 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 peculiarities of the pathological process.
• Diseases in which heredity is a causal factor, but certain manifestations of the external environment are necessary for its manifestation, their inheritance is not subject to the laws of Mendel (non-menstruating diseases); They are called multi-toric.

Hereditary diseases

The development of each individual is the result of the interaction of genetic and environmental factors. A set of human genes is established during fertilization and then, together with environmental factors, determines the characteristics of development. The body of genes in the body is called the genome. The genome as a whole is very stable, but under the influence of changing environmental conditions there may be changes in it - mutations.

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

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

Genes are located along the chromosomes linearly, and each gene occupies a strictly defined place (locus). Genes that occupy homologous loci are called allelic. Each person has two alleles of the same gene: one for each chromosome of each pair, with the exception of most genes on chromosomes X and Y in men. In cases where the same alleles are present in the homologous regions of the chromosome, they speak about homozygosity, and when they contain different alleles of the same gene, it is customary to speak of heterozygosity for this gene. If a gene (allele) exerts its effect, being present only in one chromosome, it is called dominant. The recessive gene is manifested only if it is present in both members of the chromosomal pair (or in a single chromosome X in men or women with the X0 genotype). A gene (and its corresponding trait) is called X-linked if it is located on chromosome X. All other genes are called autosomal.

Distinguish between dominant and recessive inheritance. In the case of dominant inheritance, the trait manifests itself in both homozygous and heterozygous states. In the case of recessive inheritance, phenotypic (a set of external and internal features of the body) manifestations are observed only in the homozygous state, while they are absent with heterozygosity. A sex-linked dominant or recessive mode of inheritance is also possible; in this way, traits associated with genes located on sex chromosomes are inherited.

When dominant inherited diseases usually affect several generations of the same family. With recessive inheritance, a latent heterozygous carrier state of the mutant gene can exist for a long time in the family, and therefore sick children can be born from healthy parents or even in families that have not had the disease for several generations.

Hereditary diseases are based on gene mutations. Understanding of mutations is impossible without a modern understanding of the term "gene". Currently, the genome is considered as a multigenomic symbiotic construct consisting of obligate and optional elements. The basis of obligate elements is constituted by 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 term “gene” includes the transcribed region: exons (the actual coding region) and introns (a non-coding region that separates the exons); and flanking sequences - leader, preceding the beginning of the gene, and tail untranslated region. Optional 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 required. This DNA can participate in the regulation of gene expression, perform structural functions, increase the accuracy of homologous mating and recombination, and contribute to the successful replication of DNA. The participation of elective elements in the hereditary transmission of characters and the formation of mutational variability is now proven. Such a complex structure of the genome determines the diversity of gene mutations.

In the broadest sense, mutation is a stable, inherited change in DNA. Mutations may be accompanied by changes in the structure of chromosomes that are visible during microscopy: deletion is the loss of a portion of a chromosome; duplication - doubling of the chromosome region, insertion (inversion) - rupture of the chromosome region, its rotation by 180 ° and attachment to the place of rupture; translocation - separation of a part of one chromosome and its attachment to another. Such mutations have the greatest damaging effect. In other cases, mutations may involve the replacement of one of the purine or pyrimidine nucleotides of a single gene (point mutations). These mutations include: missense mutations (mutations with a change in meaning) - replacement of nucleotides in codons with phenotypic manifestations; nonsense mutations (meaningless) - nucleotide substitutions at which termination codons are formed, as a result, the synthesis of the protein encoded by the gene is terminated prematurely; splicing mutations are substitutions of nucleotides at the junction of exons and introns, which leads to the synthesis of extended protein molecules.

Relatively recently, a new class of mutations has been identified - dynamic mutations or expansion mutations associated with instability in 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 no phenotypic disorders are observed (that is, the disease does not develop). A disease develops only when the number of repetitions in these sites exceeds a certain critical level. Such mutations are not inherited according to the law of Mendel.

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

All hereditary diseases can be divided into three large groups:

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

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

[1], [2], [3], [4]

Classification of hereditary diseases

Chromosomal	Monogenic	Multifactorial (polygenic)
Anomalies of the number of sex chromosomes: - Shereshevsky-Turner syndrome; - Kleinfelter syndrome; - Trisomy X syndrome; - Syndrome 47, XYY Autosome: - Down syndrome; - Edwards syndrome; - Patau syndrome; - partial trisomy 22 Structural anomalies of chromosomes: Feline cry syndrome; 4p deletion syndrome; Syndromes of microdeletion of neighboring genes	Autosomno-dominant: Marfan syndrome; von Willebrand disease; Anemia Minskskogo-Shophfara and others Autosomal recessive: - phenylketonuria; - galactosemia; - cystic fibrosis, etc. X-linked recessive: Hemophilia A and B; Myopathy Dushena; And etc. X-linked dominant: - Vitamin D-resistant rickets; - brown color Tooth enamels, etc.	CNS: some forms of epilepsy, schizophrenia, etc. Cardiovascular system: rheumatism, hypertensive illness, atherosclerosis, etc. Skin: atopic dermatitis, psoriasis, etc. Respiratory system: bronchial asthma, allergic alveolitis, etc. Urinary system: urolithiasis, enuresis, etc. The digestive system: peptic ulcer, ulcerative colitis, etc.

Chromosomal diseases can be caused by quantitative chromosome abnormalities (genomic mutations), as well as structural chromosome abnormalities (chromosomal aberrations). Clinically, almost all chromosomal diseases manifest as impaired intellectual development and multiple congenital malformations, often incompatible with life.

Monogenic diseases develop as a result of damage to individual genes. The majority of hereditary metabolic diseases (phenylketonuria, galactosemia, mucopolysaccharidoses, cystic fibrosis, adrenogenital syndrome, glycogenosis, etc.) belong to monogenic diseases. Monogenic diseases are inherited according to the laws of Mendel and can be divided into autosomal dominant, autosomal recessive and linked to chromosome X by the type of inheritance.

Multifactorial diseases are polygenic, for their development requires the influence of certain environmental factors. The common symptoms of multifactorial diseases are as follows.

• High frequency among the population.
• Pronounced clinical polymorphism.
• The similarity of the clinical manifestations of the proband and the next of kin.
• Age and sex differences.
• Earlier onset and some amplification of clinical manifestations in downward generations.
• Variable therapeutic efficacy of drugs.
• The similarity of the clinical and other manifestations of the disease in the immediate family and the proband (the coefficient of heritability for multifactorial diseases exceeds 50-60%).
• The inconsistency of the laws of inheritance to the laws of Mendel.

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 can not be attributed to those congenital diseases that occur during critical periods of embryogenesis under the influence of adverse 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 laying of the heart (I trimester of pregnancy), for example, a viral infection, tropic to the tissues of the developing heart; alcohol syndrome of the fetus, abnormal development of the limbs, ears, kidneys, digestive tract, etc. In such cases, genetic factors form only hereditary predisposition or increased susceptibility to the action of certain environmental factors. According to the WHO, developmental abnormalities are present in 2.5% of all newborns; 1.5% of them are caused by the action of adverse exogenous factors during pregnancy, the rest are mainly of a 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.

[5]

Methods of diagnosis of hereditary diseases

Currently, practical medicine has a whole arsenal of diagnostic methods that allow to identify hereditary diseases with a certain probability. The diagnostic sensitivity and specificity of these methods are different - some allow only to suggest the presence of the disease, others with great accuracy identify mutations underlying the disease or defining the features of its course.

[6], [7], [8], [9]

Cytogenetic methods

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

• research of sex chromatin - determination of X- and Y-chromatin;
• karyotyping (karyotype - a combination of cell chromosomes) - determining the number and structure of chromosomes in order to diagnose chromosomal diseases (genomic mutations and chromosomal aberrations).

[10], [11], [12], [13],