Cardiomyopathies (CMP) is part of a heterogeneous group of cardiac muscle diseases. In recent years, a large number of studies have been aimed at finding genetic variants associated with the CMP. Genetic markers were identified mainly for monogenic forms of the disease, and little is known about the role of modifier genes, and the results are often contradictory. Progress in studying the molecular and genetic processes that underlie the development of the CMP gives important information for clinical cardiology. Establishing an etiological diagnosis can directly affect the course, prognosis of the disease and treatment of patients. Genotype-based diagnosis of CMP allows to identify patients who are at risk of developing the most serious complications and outcomes of this disease. With the development of new sequencing technologies, the correct interpretation of the results of genetic analysis takes on special importance, which requires from the cardiologists and geneticists knowledge in the field of the latest achievements in genetic testing, data on newly discovered variants and clinical correlations, and understanding of the complexity of allelic heterogeneity characterizing hereditary cardiomyopathies. The purpose of this work is to systematize and summarize the results in the field of clinical and molecular genetic studies of CMP and to assess the possibilities of using high-tech methods for studying the human genome in practical medicine for diagnosis and targeted treatment of CMP.

Introduction: Phenylketonuria (PKU) - a hereditary metabolic disease that arises from mutations in the PAH gene, the part of the program of neonatal screening in the Russian Federation. Patients with PKU need to follow a diet for life, limiting the intake of natural protein in the body to prevent the development of clinical manifestations of the disease, the main of which is a delay in mental development. Data on the genotype of patients with PKU make it possible to predict their sensitivity to the cofactor therapy, which allows to expand significantly the diet and improve the quality of life. Patients and methods: The study was conducted between December 2016 and January 2018 at the DNA Diagnostics Laboratory of the Federal State Budgetary Institution «Research Centre for Medical Genetics». Material from 1254 unrelated probands was examined for the presence of 25 frequent mutations of the PAH gene. Results: Pathogenic variants are revealed on 86,3% of the investigated chromosomes. In 75.3% of patients, the diagnosis of «phenylketonuria» caused by mutations in the PAH gene was confirmed by molecular genetic methods. Only one pathogenic variant was found in 22.1% of probands, 2.6% did not reveal pathogenic variants of the PAH gene. The allelic frequencies of 25 frequent mutations of the PAH gene are determined. Regional differences in the prevalence of the R408W mutation, as well as the heavy and soft mutations of the PAH gene, are revealed. According to the results of the study, 56.9% of patients are «non-responders» to BH4 therapy, 21.8% - are potential «responders». Discussion: Using the Hardy-Weinberg ratio, we can calculate the total allelic frequency of 25 mutations and the frequency of R408W, calculate the number of patients with mutations in the BH4 synthesis and metabolism genes and the number of R408W homozygous patients not included in the genotyping program.

The Waardenburg syndrome (WS) is a rare autosomal dominant disease with varying phenotypic manifestations and heterogeneous genetic control characterized by hearing loss and pigmentation impairments of skin, hair and iris. 514 patients with congenital hearing impairments from 484 families were examined in the Sakha Republic of Russia and three patients with phenotypes corresponding to the WS from two families were identified, thus, the frequency of the WS among patients with congenital hearing impairments in the Sakha Republic is 0.62% (3/484). To search the molecular genetics causes of the WS in these patients Sanger sequencing of the coding fragments of genes PAX3 , MITF , SOX10 and SNAI2 was performed. The synonymous heterozygous substitutions were found in two members of one family with WS type I: in daughter - c.804C>T (p.Asn268Asn) in gene PAX3 and in her father - c.927C>T (p.His309His) in gene SOX10 . Both variants c.804C>T (p.Asn268Asn) and c.927C>T (p.His309His) are likely not pathogenic. Heterozygous transition c.772C>T in exon 8 of gene MITF, previously known in association with the WS, was found in one patient with the WS type II. The c.772C>T variant leads to premature stop codon (p.Arg259*) terminating translation of MITF. A patient with a nonsense variant c.772C>T (p.Arg259*) in gene MITF was characterized by a rare phenotype of the WS type II: congenital unilateral hearing loss (deafness in left ear, normal hearing in right ear) and unilateral heterochromia of irises (dark brown right eye, brilliant blue left eye). The results confirm the association of the MITF mutations with the WS type II and expand the information on phenotypic variability of this syndrome.

The article describes the results of application of the two most common commercial non-invasive prenatal tests (NIPTs), Harmony and Panorama. The pregnant women were divided into the high and low risk groups due to prenatal screening of the first trimester results. A total number of cases: 5,076 (1710 Harmony and 3366 Panorama), of which 592 twins. High-risk group: 2921 patients: 1926 (Panorama) and 995 (Harmony); low risk group: 2155: 1440 (Panorama) and 715 (Harmony). The high risk of chromosome pathology of the fetus according to the results of NIPT was determined in 144 observations, including 89 for trisomy 21, 14 for trisomy 18, 10 for trisomy 13 and 26 - for the pathology of sex chromosomes. Prenatal karyotyping was performed for 134 patients: for 110 cases chromosomal abnormalities were detected, in one case the patient refused to perform invasive prenatal test (newborn was diagnosed with trisomy 21). For 4,930 patients with low risk of chromosomal pathology of the fetus in according to the, childbirth was completed with a child with normal phenotype. cffDNA for two false-negative cases was less 4.6%. The calculated values of the sensitivity, specificity, and the positive (PPV) and negative (NPV) predictive values in the complete group of tested without stratification for the risk of chromosome pathology of the fetus, calculated from the prenatal screening of the first trimester, were 95.2%, 99.3%, 64.5% and 99.9%, respectively, for Harmony and 98.9%, 99.4%, 83.6%, 99.9% for Panorama, which corresponds to the manufacturer’s specifications. In the group of patients with high risk for prenatal screening of the first trimester, the values of the PPV and NPV were 85.6% and 99.9% for Panorama, respectively, while 73.9% and 99.9% for Harmony. For the group of low-risk patients: for the Panorama a PPV was 78.9%, while NPV was 100%; for the Harmony NPV was 100%, while the PPV - 37.5%. For low-risk women group in both NIPTs low NPV is mainly owing to the presence of false positive results for X monosomy. The obtained results indicate that it is not rationally to perform NIPT to detect aneuploidy on sex chromosomes, especially in the low-risk group for chromosomal pathology the fetus.

Relevance . In many populations of patients with hypertrophic cardiomyopathy (HCM), mutation of р.Gln1233* (rs397516037) and р.Arg326Gln (rs34580776) substitution in MYBPC 3 have been identified with different frequency. The published data of these genetic changes differ in the interpretation of their pathogenicity. The founder effect has been described for р.Gln1233* for some populations. The aim was to assess the incidence of rs397516037 and rs34580776 substitution in MYBPC 3 in Belarusian patients with HCM and in control group; to test the hypothesis about the effects of the founder for р.Gln1233* mutation, and to describe clinical features of the disease in the group of patients with this mutation. Materials and methods . Genetic analysis was made by NGS for 85 individuals. A guided search for a р.Arg326Gln substitution by PCR-RFLP was made in 250 non-related individuals, 13 proband relatives with р.Gln1233* mutations and 127 controls. The р.Gln1233* mutation identification was made using automated sequencing method in all carriers of р.Arg326Gln , and in 113 individuals without the substitution. In those carriers with at least one substitution, р.Val849Val (c.2547C>T, rs3729953) and р.Glu1096Glu (c.3288G>A, rs1052373) loci were genotyped by PCR-RFLP to identify the haplotype. Results . In 5.37% (18 of 335) Belarusian individuals with HCM, р.Gln1233* nonsense-mutation and р.Arg326Gln substitution in cis-arrangement were established. No р.Gln1233* mutation in the controls suggested its diagnostic significance concerning the development of HCM. The р.Arg326Gln substitution without present р.Gln1233* mutation was established in 5.07% (17 of 335) individuals and in 3.94% controls of the sample suggesting the insignificance of this polymorphism in the development of the condition. The effect of the founder for р.Gln1233* mutation for Belarus has been established. Clinical characteristics of HCM has been proposed for probands and closest relatives who have this mutation. Conclusions . р.Gln1233* nonsense-mutation (rs397516037) is the most frequent mutation among mutations identified in Belarusian individuals diagnosed with HCM. The course of the disease in p.Gln1233* carriers varied from mildly symptomatic at a younger age (18 to 40 y.o.) to severe with malignant prognosis including fatal outcome due to CHF progression.

Myotonic dystrophy (MD) is a common form of muscular dystrophy in adults with autosomal dominant inheritance, characterized by progressive myopathy, myotonia, multiorgan involvement. There are two types of the disease: myotonic dystrophies 1 and 2. Both types are repeat expansion diseases. MD1 is caused by an increase CTG-repeats in the 3’-untranslated region of the DMPK gene on chromosome 19, MD2 - by an increase of CCTG-repeats in intron 1 of the ZNF9 gene on chromosome 3. The phenomenon of anticipation is described for myotonic dystrophy type 1 but not for MD2. Modifying factors are being searched actively in recent years. A sample of FSBI RCMG patients with clinical diagnosis «myotonic dystrophy» was analyzed in this study. Tendencies of the influence of gender as a modifier of the disease severity have been revealed. The proportion of MD2 in the myotonic dystrophies among Russian patients has been established as 17%. Earlier it was supposed that this form might be very rare.

Mutations in the CCM genes causing the formation of cavernous malformations (СМ) are being actively studied and their list is constantly growing. Mutations in the CCM genes are usually analyzed using two main approaches: multiplex ligation-dependent probe amplification (MLPA) - to search for large deletions/insertions and exon sequencing - to search for mutations leading to amino acid substitutions, the appearance of premature translation termination, reading frame shifts and splice site junction. On the basis of these data, cheaper diagnostic test systems are created that allow the identification of mutant alleles in order to predict the possible occurrence and development of cerebral cavities. Objective. Identification of large deletions in CCM genes associated with the developing of cerebral СМ in patients with sporadic and hereditary forms of the disease in the Russian population. Methods. Blood samples from 92 selected patients were examined, among them - 45 with a hereditary form of the disease, 2 - with clinically confirmed familial cases and 45 - so-called sporadic cases, as well as in 10 healthy relatives. Presence of large deletions/duplications was detected by multiplex ligation-dependent probe amplification (MPLA). Results. Major rearrangements in one of the CCM genes ( CCM1 , CCM2 , CCM3 ) were identified in 10 samples, including 2 patients with conditionally familial form of CM, and 3 patients with a sporadic form. Of the seven types of mutations identified, four were not previously described. Two deletions in the CCM3 [PDCD10] gene were identified, for which such mutations have not yet been described. The ratio of mutations in the CCM1 , CCM2 and CCM3 genes was 40%, 30% and 30%, respectively. The most aggressive clinical course was observed in patients with mutations in the CCM3 gene. Conclusion. The analysis showed that large deletions in the genes of CCM are quite common in patients with sporadic and hereditary forms of the disease in the Russian population and accounted for approximately 11% of the studied sample. At the same time, new types of mutations that are not described in other populations have been identified

We present the first clinical observation of a 23 years old patient with a juvenile form of Krabbe disease in Russia. We also review current knowledge on the etiology, pathogenesis, clinical manifestations, and management of the Krabbe disease with late onset in general. Challenges in differential diagnosis are discussed, particularly in the cases with Krabbe disease manifestation after one year of age.