Methods for diagnosing monogenic hereditary diseases

Until recently, the diagnosis of monogenic hereditary diseases was based exclusively on the features of the phenotypic manifestation of the disease. Only in some hereditary metabolic diseases, diagnostics were performed, determining the level of altered metabolites or even an altered enzyme. The phenotypic level of diagnosis was sometimes sufficient to address some of the problems of clinical genetics, for example, the choice of tactics for treating clinically similar but genetically very heterogeneous diseases, such as neuromuscular diseases or retinal pigmentary degeneration.

It should also be noted that the treatment in these cases was purely symptomatic. Advances in the field of molecular genetics allow for many monogenic diseases to translate the diagnosis to the level of determining changes in the genotype. It follows from the preceding text of the chapter that such DNA diagnostics in some cases fundamentally changes the concept of classification of hereditary diseases and opens new possibilities for the pathogenetic treatment of hereditary diseases. In addition, DNA diagnosis is a powerful tool for prenatal diagnosis of hereditary diseases.

All methods of DNA diagnosis of hereditary diseases can be divided into direct and indirect. Both direct and indirect methods of DNA diagnostics are very diverse. Direct methods of analysis have a number of advantages. For them, there is no need to study other family members or consider possible recombinations in the gene. There is also a problem of insufficient information content of genetic markers.

The main indirect method of DNA diagnosis of hereditary diseases is the analysis of the linkage using genetic markers to search for the linkage with the gene of the disease to a variety of DNA polymorphisms. The linkage analysis can be applied to any charted gene of the hereditary disease. It does not require the study of the fine structure of the mutant gene. DNA markers allow us to establish whether an individual has inherited a chromosome carrying a mutant gene or not. The adhesion method has a number of drawbacks, among which is the need to investigate a large number of the patient's relatives in order to establish with which alleles and which marker the disease gene is linked;the need to take into account the possibility of crossing-over( cross-over) between DNA markers and the disease genome, which makes it impossible to be 100% sure of the diagnosis of the disease. The latter is achieved by using direct methods.

Phenotypic signs that medical genetics deals with are hereditary diseases and their symptoms. Between the symptoms of a hereditary disease and the change of one protein as a result of a mutation in a particular gene, the distance is huge. A mutant protein, the product of a mutant gene, must somehow interact with hundreds, if not thousands of other proteins encoded by other genes, to change some normal trait or a pathological symptom. In addition, gene products involved in the development of any phenotypic trait can interact with and modify environmental factors.

Monogenic hereditary diseases are inherited according to the rules established by G. Mendel. There are autosomal dominant and autosomal recessive hereditary diseases. Pedigrees of families in which diseases are inherited in this way have a number of distinctive characteristics. There are also strict methods of proving dominant or recessive inheritance of diseases.