Methods of diagnosing hereditary diseases

Clinical and genealogical methods

The first stage of diagnostics often begins with an examination and taking a medical history. The clinical-syndromological method makes it possible to detect characteristic morphological, biochemical, and functional signs of hereditary pathologies. Classic examples of applying this approach include:

• Detection of plasma factor VIII deficiency in hemophilia A.
• Determination of the 45,X0 karyotype in Turner syndrome.
• Discovery of combined skeletal, cardiovascular, and ocular lesions characteristic of Marfan syndrome.

To understand how a disease is transmitted within a family, the clinical-genealogical method is used. Its essence lies in carefully identifying pathological signs in relatives and tracing the patterns of their transmission by compiling a detailed pedigree. This method serves several crucial purposes:

1. Determining the inheritance pattern (dominant or recessive, as well as autosomal or gonosomal, i.e., sex-linked).
2. Identifying hidden carriers of the gene responsible for the development of the disease.
3. Assessing the degree of penetrance — the frequency of the actual manifestation of a trait in mutation carriers.
4. Determining the degree of genetic risk, i.e., the probability of having an affected child.

Assessment of environmental role and biological modeling

To understand what contributes more to the development of a pathology — genetics or external conditions — the twin method is used. It is based on a comparative analysis of the frequency of a certain trait in different groups of twins. The physician compares monozygotic twin partners with each other, and also compares them with dizygotic pairs and the general population. Key concepts here are concordance (complete identity of twins regarding the analyzed trait) and discordance (their difference). The final assessment of the role of heredity and environmental factors is calculated using special mathematical formulas.

For a more in-depth analysis of pathogenesis, the biological modeling method is used. The objects of study are animals — both healthy and mutant. Modeling pursues three main goals:

• Detailed analysis of possible genetic defects occurring in humans.
• Study of mutagenic and teratogenic effects of various medications and other chemical or physical agents.
• Development and testing of new genetic engineering methods.

Laboratory diagnostics: from cell to DNA molecule

Modern genetics relies on high-precision laboratory technologies that can be divided into several levels:

• Cytogenetic diagnostics (karyotyping). The method is based on the microscopic study of chromosomes in order to identify their structural abnormalities. Tissue cultures with a large number of actively dividing cells are used as material. In clinical practice, peripheral blood lymphocytes are most commonly used for this purpose.
• Biochemical diagnostics. Aimed at identifying deviations in biochemical indicators that reflect the very essence of the disease. The objects of analysis are the activity of specific enzymes, the presence of pathological metabolites in body fluids, and the concentration of components in various enzymatic reactions.
• Somatic cell genetics. Includes complex cellular manipulations outside the body: hybridization, selection, and cell cloning.
• Molecular-genetic method (DNA diagnostics). The deepest level of analysis. Its goal is to establish the slightest changes in the nucleotide sequence, study gene structure, and confirm the presence of specific genes. The main methods of molecular diagnostics include polymerase chain reaction (PCR), DNA cloning, as well as various options for DNA hybridization (including blot hybridization and in situ blotting).

Class and exam questions

What else to study on this topic

• Features of autosomal and gonosomal inheritance patterns
• Somatic cell genetics methods: hybridization, selection, and cloning
• Polymerase chain reaction (PCR) technology in medical genetics
• DNA blot hybridization and in situ blotting: principles of the methods
• Calculation of genetic risk based on pedigree

Other topics in chapter "Chapter 3. Forms of pathology caused by changes in the genome"

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