The concept of genetic heterogeneity of hereditary diseases is discussed in the article in details. It describes the types of genetic heterogeneity and it’s reasons at the molecular level. The most appropriate approach for the diagnosis of hereditary diseases is DNA diagnostics. The main purpose of DNA diagnostics is the determination of the causal mutation in a particular family. The types of DNA diagnostics, depending on the methodological approaches are considered. However, genetic heterogeneity of hereditary diseases complicates the medical genetic counseling of each family. So the optimization of the DNA diagnostic procedures is needed. The approaches for the optimization of DNA diagnostic for diseases groups with different types of inheritance are considered. Mutations searching in the «hot» spots and «hot» exons in genes responsible for the pathology development is essential for autosomal dominant and X-linked disorders. For the autosomal recessive diseases, it is necessary to study the mutation spectrum in various regions of the Russian Federation and to create region-adapted diagnostic protocols aimed at detecting of common mutations by simple methods. For diseases with a broad genetic heterogeneity, large size genes and in the case of absence of frequent mutations it is necessary to use next-generation sequencing methods. The basic points of the «DNA diagnosis on-line» concept implemented in DNA diagnostics laboratory of Research Centre for Medical Genetics to identify the molecular causes of monogenic diseases in burdened families are described.

Limb-girdle muscular dystrophy (LGMD) 2L is caused by mutations in the ANO5 gene and is predominantly distributed in Northern Europe and Finland. There are two major mutations in European population: c.191dupA (p.Asn64Lysfs) and c.2272C>T (p.Arg758Cys), which leading to LGMD 2L and Miyoshi muscular dystrophy, type 3. This two common mutations were analyzed in the cohort of Russian LGMD patients comprising 480 samples from different areas of Russian Federation. Four patients were heterozygous and one patient was homozygous for the c.2272C>T mutation. The c.191dupA mutation wasn’t found. A c.173G>A (p.Arg58Gln) mutation and a novel с.412G>T (p.Gly138Stop) mutation were identified in heterozygous status in one case each. LGMD 2L accounts at least 0,6% in a Russian LGMD cohort. The prevalence of LGMD2L in Russian Federation was estimated at least 1:120000 with 95% confidence intervals of 1:20000 to 1:825000.

Spinal muscular atrophy (SMA) is one of the most severe autosomal recessive disorders. SMA gene has been mapped to chromosome 5q12.2-q13.3. Gene codes for a survival motor neuron protein (SMN). It has the telomeric and centromeric copies. SMA is caused by mutation in the telomeric copy of SMN gene ( SMNt ). New quantitative method of copy number analysis of SMA locus genes has been developed and introduced into practice at the Research Centre for Medical Genetics. This method is based on Multiplex Ligase Probe-Amplification. The SMA Carrier screen was carried out in 432 patients.

Since 01.01.2014 to 01.03.2016 the most common FXN gene mutation was investigated in 201 patients of DNA Diagnostics Laboratory of the Research Centre of Medical Genetics. There are results in current study. The new medical technology introduced into practice at the Centre of Medical Genetics was used. It was found that this technology makes more effective a medical and genetic counseling of families affected by Friedreich’s ataxia. It permits to carry out genetic test of Friedreich’s ataxia, including carrier screening for proband’s relatives and prenatal diagnosis, more quickly and with lower maintenance costs.

The molecular genetic study of 180 probands with phenylketonuria, directed to the DNA-diagnostics laboratory of FSBI «RCMG» in the period from 10.01.2015 to 01.02.2016. New medical technologies embedded into practice FSBI «RCMG» were used for DNA diagnostics. It was found that the application of these technologies makes the medical and genetic counseling of families more effective. It allows to make a diagnosis in a short time and with less logistical costs. Also it is used for carrier diagnostics for the relatives of the proband and prenatal diagnosis in burdened families.

Achondroplasia and Hypochondroplasia are the most frequent form of short-limb dwarfism. Affected individuals exhibit short stature caused by rhizomelic shortening of the limbs, characteristic facies with frontal bossing and midface hypoplasia, exaggerated lumbar lordosis, limitation of elbow extension, genu varum, and trident hand. Hypohondroplasia is much milder and can be distinguished on clinical and radiographic grounds. Hypochondroplasia and achondroplasia are indeed allelic disorders that cause by mutation in FGFR3 «hot spots». The paper presents the results of DNA diagnostics 200 probands with short-limb dwarfism using embedded into practice FSBI «RCMG» new medical technology «Detection system the most frequent mutations in FGFR3 gene, liability for achondroplasia and hypochondroplasia».

Spinocerebellar ataxias (SCAs) are a group of autosomal dominant inherited disorders characterized by progressive cerebellar ataxia and variable findings. SCAs are classified genetically according to a specific mutation or mapped locus, and also based on the clinical data. There are now more than 30 known genes responsible for spinocerebellar ataxia. SCAs are caused by a polyglutamine trinucleotide repeat CAG expansion. The symptoms of SCA are vary in individual patients and even within the same family. The results of the DNA diagnostics 335 probands with Spinocerebellar ataxia and their families, using of the new medical technology «the detection system in one tube, the frequent mutations in ATXN1, ATXN2, ATXN3 genes in spinocerebellar ataxia», are presented in the research.