Human population genomics is a powerful modern approach in population genetics based on technologies of genomic sequencing, bioinformatics, and big data analysis. Genomic analysis of genetic variability in populations is a fundamental basis for the genetics of diseases and the development of ways for their diagnosis, therapy and prevention. The work presents the own data on the genomic analysis of the genetic diversity of the Russian populations. It is shown that the gene pool of modern populations of Russia was formed over many thousands of years by the combined effects of migrations, isolation by distance, founder effects and natural selection. The genomic patterns of modern populations formed during microevolution substantially determine the composition of genetic factors of both frequent chronic and rare monogenic diseases.

The contribution of Turkic genetic component to the gene pool of various ethnic groups of Dagestan and the North Caucasus, which is present not only in Turkic-speaking populations, but also in neighboring ones, is revealed. In the mountain populations of Dagestan, unlike the plains, the Turkic component is almost completely absent.

The contribution of the Mongolian component to the gene pool of various ethnic groups of Siberia, Central Asia and the Volga-Ural region, which is present in the Mongol-speaking and Turkic-speaking ethnic groups, is revealed. An analysis of the composition of the various sublines of the Y-chromosome haplogroups shows that the introduction of this genetic component was associated with time-varying migration events and tribal groups of different origin.

The results of genetic and epidemiological studies of hereditary diseases (HD) in 14 regions of the European part of Russia, the South of Russia, the North Caucasus, the Volga-Ural region, with a total population of about 4 million people surveyed were analyzed. Spatial variability and genetic heterogeneity of HD in the population of different regions and in multi-ethnic populations of Russia have been studied. Frequent HD that are typical for the entire population of specific regions, as well as diseases specific to individual ethnic groups were identified. Significant heterogeneity of populations and ethnic groups, both allelic and locus, has been detected. Novel previously undescribed HD which are endemic for specific ethnic groups have been registered. It was shown that in populations with different ethnic extraction each ethnic group in its gene pool has preserved specific spectrum, prevalence and genetic nature of HD. Complex multifaceted analysis allowed us to approach the fundamental problem of medical genetics - the evolution of HD in different populations and ethnic groups.

At the present time the most dramatic changes in the epidemiology of hereditary diseases is the transition from theoretical principles of population genetics in public health to the active use of molecular genetic technologies for individuals. Genetic discoveries are the basis of individualized medicine, as well as the source of new knowledge about the load of hereditary diseases in populations with their subsequent translation into healthcare system.

On the basis of archival data from the laboratory of genetic epidemiology of the RCMG for 11 Russian populations, a method for quantifying the genetic heterogeneity of populations based on the load of autosomal dominant and autosomal recessive hereditary pathology is proposed. It is shown that the Krasnodar region is characterized by the least heterogeneity, and the population of Tatarstan is the largest.

Results of a study (1980-2019) on dynamics of reproduction indices, female reproductive parameters and morbidity structure in indigenous peoples - Nenets, populating Yamal-Nenets Autonomous Region are discussed.

The genomic data analysis (~907750 autosomal SNPs) allowed us to estimate the inbreeding level based on the analysis of runs of homozygosity (Froh) in the group of 518 people from 23 indigenous Dagestan peoples. As a result, the number and total length of ROH, as well as the FROH coefficient, show a significant diversity in the indigenous Dagestan populations both inside and between them. One of the highest values of the inbreeding coefficient (FROH> 1.5Mb) is observed for the Ginukhs, Gunzibians, Akhvakhs, Bezhtins, and Tsez, as compared with the other world populations.

Inbred marriages are traditionally popular among the population of Azerbaijan, in the spread of which various religious, national traditions, rites and prejudices play an important role. The birth of children with various congenital malformations from year to year not only does not decrease, but in some cases even tends to increase. In the presence of a pathological recessive gene in the family of a married couple with consanguinity, the risk of having a sick child is 25%. Therefore, the problem of inbred marriages requires a more in-depth study together with doctors of various specialties. In this paper, we studied the prevalence of inbred marriages and assessed the possibility of their influence on the formation of the health of children born from these marriages.

The analysis of the prevalence of rare (orphan) diseases («List of 24») and the dynamics of detection of children’s patients in 85 subjects of the Russian Federation in the period 2013-2019 showed an annual increase in patients in the Federal register (2013 - 4962 patients, 2014 - 6761, 2015 - 7038, 2016 - 7625, 2017 - 8245, 2018 - 8639, 2019 - 9088). The dynamics of the share of children with diseases from the “List of 24” among all patients fluctuated within small limits (on average 50%). Most of the diseases (16 out of 24) are mostly between children, but they also occur in adults. The prevalence of diseases varied significantly between the subjects of the Russian Federation. Improving awareness, as well as maintaining a Federal register promote effective detection and timely treatment in children. However, the low prevalence of diseases that occur before the 1st year of life indicates the complexity of their diagnosis and lack of detection.

The aim of current research is to estimate the heterozygote carrier frequency of often found mutations. After genotyping of 120 samples from healthy individuals of yakut ethnic group 5 carriers of mutation in CUL7, 4 carriers of mutation in NBAS, 6 carriers of mutation in DIA1 and 8 carriers in GBJ2 were revealed. The results confirming once again the data previously described by other authors and indicate a high frequency of mutation carriage in the studied genes in population of yakut origin.

The Republic of Sakha (Yakutia) is one of the largest centers of accumulation of type 1 spinocerebellar ataxia in the world. In 1997, the prevalence of the SCA1 mutation among Yakuts was 35 cases per 100,000 population, and now this indicator has increased to 77.6 cases. A significant increase in the prevalence rates of SCA1 can be explained by the introduction of a family case accounting system and modern molecular genetic methods for the diagnosis of mutations. On the other hand, the monitoring results indicate the ongoing accumulation of mutations in the Yakut population. In addition, it was found that the boundaries of the known geographical centers of mutation accumulation were expanded and an assumption was made about the population heterogeneity of mutation carriers by the number of CAG repeats.

The results of congenital malformations monitoring in 23 regions of the Russian Federation for the period from 2011 to 2018 are presented. There is an increasing tendency of the overall frequency of congenital malformations from 84.18 per 10000 births in 2011 to 102.18 in 2018. Estimates of the baseline of selected defects are obtained, which should be used as the expected frequency during planning the volume of medical care for newborns with congenital malformations.

The article presents the results of monitoring of congenital anomalies of the Republic of Moldova - the national register of Moldova, formed on the basis of the laboratory of prevention of hereditary pathology at the Institute of Mother and Child. The analysis of data for the period from 2009 to 2018. The article presents data on the epidemiology of congenital anomalies: population frequencies of all registered defects and individual nosological forms, the structure of developmental defects in the country, as well as the dynamics of the frequency of defects of mandatory accounting for the analyzed period of time.

Congenital malformations of the cardiovascular system (СHD) rank first among the causes leading to infant and child mortality, as well as disability. It was revealed that in the structure of congenital malformations in Novosibirsk region, 37.3% are CHD. The average term for prenatally detecting CHD was 23.9 ± 2.3 weeks of gestation. There was an increase of ventricular septal defects by 118%, transposition of great vessels by 61%, and atrial septal defects by 37% during the observation period. In the structure of infant mortality, CHD accounted for 35.12%.

Congenital malformations make a significant contribution to the structure of child morbidity, infant mortality and disability. Data collection on congenital malformations was perfomed according to the European standard in accordance with the international classification of diseases (ICD-10). It was shown that the average frequency of congenital malformations in the region for the period 2000-2019 was 35.05‰. The first place among congenital malformations in Ivanovo oblast is occupied by congenital heart disease (27,8%), hypospadias (18,1%) and down syndrome (18,1%). All families registered in the register of congenital malformations were invited for medical and genetic consulting in order to conduct periconceptive prevention and to draw up a prenatal diagnosis plan.

A 20-year experience of monitoring the birth rates of children with congenital pathology is summarized and a set of measures is proposed to preserve the reproductive health of the population receiving medical care in the institutions of the FMBA of Russia.

Mutations in the SLC26A4 gene are a common cause of hearing loss in many regions of the world. This paper presents the results of molecular genetic analysis (by Sanger sequencing) of the SLC26A4 sequence, first performed in the sample of patients with hearing loss of unknown etiology (n=232) from the Tyva Republic and the Altai Republic. Contrast differences of the pathogenic contribution of SLC26A4 mutations to the etiology of hearing impairment were revealed in the indigenous peoples of these geographically close regions: 28.2% for Tuvinians and 4.3% for Altaians. Both known and novel pathogenic variants as well as a wide range of polymorphic variants were found in the SLC26A4 gene sequence.

We presents the results of audiological, radiological and molecular genetic studies of 165 patients with congenital hearing impairment in Yakutia to investigate of autosomal recessive form of deafness associated with anomalies of the inner ear (IP-I, IP-II and / or EVA) and mutations in the SLC26A4 gene (DFNB4, MIM 600791).

Non-syndromic hearing loss (NSHL) is one of the most prevalent inherited sensory disorder, mutations in GJB2 gene represent a major cause of NSHL worldwide. The aim of the work was to determine frequency mutations in GJB2 gene among 642 participants from a population-based cohort study ESSE-Vologda. Genotypes were determined by the TaqMan OpenArray Genotyping platform on the QuantStudio 12K Flex Real-Time PCR System. The genotypes of 642 samples were determined and 39 carriers of mutations in the GJB2 gene were detected, the frequency of heterozygous mutations in the sample was 6.07% (CI95%: 4.36-8.21%) or 1:16. The high frequency mutations in the GJB2 gene associated with NSHL indicates the potential for preventive screening in young families planning children.

We present the results of a complex assessment of the pathogenetic significance of novel variant c.516G>C (p.Trp172Cys) of the GJB2 gene found with high frequency in deaf patients from the Tyva and Altai Republics. Several lines of evidences support pathogenicity of this variant due to its damaging effect on the structure and functioning of connexin 26 (Cx26).

The paper presents the results of an analysis of the prevalence of sign language (SL) in Russia collected during the 2010 total census, as well as their comparison with data on the frequency of hereditary forms of hearing loss.

Cystic fibrosis (CF) is an autosomal recessive disease caused by impaired function of the epithelial chloride channel encoded by the CFTR gene. The spectrum and frequency of CFTR gene variants, as well as the CF incidence, vary in different countries and ethnic groups. The frequency distribution of CFTR gene variants in CF patients and in healthy individuals in the Republic of North Ossetia-Alania was studied. The spectrum of pathogenic variants in Ossetian CF patients is specific: the most frequent are two variants W1282X (50%) and F508del (20%), while in the all-Russian CF patients the most frequent are variants - F508del (52.8%) and CFTRdele2.3 (6.2%), and the variant W1282X (1.90%) is relatively rare. In healthy Ossetians, the frequencies of detected variants W1282X and F508del are 0.0032 and 0.0016, respectively. The most common CFTR gene variants are W1282X and F508del, found both in CF patients and healthy individuals from the Ossetian population of the Republic of North Ossetia-Alania.

We present improvement algorithm of newborn screening for cystic fibrosis (CF), in which oblygatory DNA-testing stage among CF-high risk newborns was incorporated alongside with traditional screening design. Such approach make it possible for early and accurate diagnostics of CF among newborns. CF frequency in Tomsk region was 1 in 5882 newborns. Allelic frequencies of the CFTR gene mutation were estimated.

Features of the spectrum of pathogenic CFTR gene variants in CF patients with negative neonatal screening compared to positive screening CF patients include a significantly higher frequency of genotypes associated with residual pancreatic function, a higher frequency of 3849+10kbC>T, and a lower frequency of F508del variant homozygotes.

The aim of the study was to create a panel for screening the carriers of mutations associated with the development of cystic fibrosis (CF), and testing the panel on 642 participants of the population-based cohort study (ESSE-Vologda). Variants were detected using the QuantStudio 12K Flex Real-Time PCR system. A custom panel that includes 60 CFTR variants was created. Among 642 participants in the study, 23 heterozygous carriers of 6 CFTR mutations were identified. The carrier frequency was 3.58% (CI95%: 2.28-5.33%) or 1:28. The custom panel can be used for screening heterozygous CF carriers.

Inborn errors of metabolism are an extensive class of genetic diseases and contribute significantly to childhood morbidity, and their diagnosis using biochemical methods is often difficult. Three panels for sequencing of 88 genes responsible for the development of three groups of inborn errors of metabolism (IEM) were developed and introduced in St.Petersburg Medical and Genetic Center and 84 children were tested for which these diseases were suspected by tandem mass-spectrometry or by the presence of clinical symptoms. In 6 children, the NGS method fully established the genetic cause of the disease. Pathogenic mutations were detected significantly more frequently with increased biochemical markers, demonstrating the leading role of pre-biochemical screening in performing NGS analysis. NGS significantly improves the clinical diagnostic effectiveness of IEM. Biochemical testing and NGS play complementary roles and their complex use in selective screening algorithm allows to increase accuracy of IEM diagnostics.

The paper presents the results of an extended genetic study of 39 children observed in the MC “Health Care of Mother and Child” (Ekaterinburg) with a «hyperphenylalaninemia». An analysis of the previously known results of the study in these patients (the p. R408W variant in the heterozygous in 13 probands) showed that the search for recurrent gene variants using the panel does not give the expected proving of the diagnosis and requires additional testing. Applying the «gold standard» of diagnosis - direct sequencing of the PAH gene, the diagnosis of phenylketonuria (PKU) was confirmed in 35 probands (89.8%) - 2 altered alleles were found in them, one pathogenic variant was found in 4 others. A study of the DNA of parents and siblings indicated a families’ variants of inheritance for all identified mutations. As a result of the study, the pathology spectrum of the PAH gene, currently in use for the population of the Sverdlovsk region, has undergone significant changes, which require a new approach to the genetic diagnosis of this hereditary pathology in the region.

The aim of the work was to create and test a custom panel of 23 PAH gene variants responsible for the development of phenylketonuria, and to evaluate the frequency of heterozygous carriers of these mutations among 642 participants of the population-based cohort study ESSE-Vologda. The presence of mutations was determined using QuantStudio 12K Flex Real-Time PCR system. 17 carriers of PAH variants among 642 participants were identified. The frequency of heterozygous carriers was 2.65% (CI95%: 1.55-4.21%), or 1:38. The data obtained indicate a high frequency of PAH variants in the Russian population. The proposed panel can be used for screening on heterozygous carriers of variants that cause phenylketonuria.

The aim of the study was to study the spectrum and identify ethnic characteristics of mutations of PAH gene in patients with PKU in Kazakhstan. The article presents the results of molecular genetic examination of 88 patients with PKU from unrelated families, including 36 patients of Kazakh nationality, 44 Russians, 5 Uighurs and 3 Uzbeks. The most frequent mutation in the PAH gene in Kazakhs was p.243Q mutation (with a frequency of 0.250), in Russians, Uighurs and Uzbeks p.R408W mutation with a frequency of 0.545, 0.400 and 0.333, respectively. Only in Kazakhs, following mutations were identified in PAH gene: IVS4 + 5G> T, IVS10-14C> G (0.028), p.V230I (0.028), p.A300S (0.014), p.W187X (0.014), p.R158Q (0.014), p.Y387H (0.014), p.I65N (0.014), p.R243L (0.014), p.Val399 = (0.014), c.326e> G (0.014), p.P119S (0.014). Mutations IVS7-3C> A and p.E390G in PAH gene were found only in Russians. For patients of Uyghur nationality, mutation p.R413P turned out to be ethnically specific; for Uzbeks, the mutations p.R261X, G188D, p.R252Q, c.826-829 ins/del4?. The results obtained allowed us to describe the spectrum and ethnic characteristics of mutations of PAH gene in Kazakhstan.

Mass examination of newborns in the neonatal screening program in the Republic of Kazakhstan is carried out for 2 hereditary diseases - phenylketonuria and congenital hypothyroidism. In 2019 pilot project was conducted for 1000 studies using tandem mass spectrometry of children under age of 1 year for 49 hereditary metabolic diseases.

The article presents a clinical case of the minisymptomatic course of Fabry’s disease in pediatric practice in adolescent girl with acroparesthesia, laboratory indicators of low glomerular filtration rate and positive family history of the underlying disease.

Fabry Disease (BF), MIM 301500 - X-linked disease caused by mutations in the GLA gene, which encodes the enzyme α-galactosidase A (α-gal A). In 2017, a method for determining the concentration of lyso-Gb3 for the diagnosis of FD was developed and introduced in the laboratory of molecular genetics and medical genomics of the “National Medical Research of Children’s Health Federal State Autonomous Institution of the Ministry of Health of the Russian Federation. To date, we have studied 9830 samples of dry blood spots from various regions of Russia, obtained from 8832 male and 998 female patients, aged 12 to 70 years. As a result of the study, a decrease in enzyme activity was detected in 33 men, and in 31 of them an increase in the concentration of lyso-Gb3, pathogenic variants of the GLA gene were found in these men, while the two remaining men found polymorphic variants of the GLA gene, previously described as alleles with pseudodeficiency activity. In addition, 2 women with an increased concentration of lyso-Gb3 were identified, in whom pathogenic variants of the GLA gene were also detected, while in 5 women with pseudo-deficient alleles of the GLA gene, the concentration of lyso-Gb3 was normal. Our study demonstrated the advantage of measuring the concentration of the lyso-Gb3 biomarker compared to determining the activity of the α-gal A enzyme for the initial diagnosis of men with suspected FD, as well as the possibility of using this biomarker for the initial diagnosis of women with suspected DF.

Gaucher disease (GD), caused by GBA mutations, encodes lysosomal enzyme glucocerebrosidase (GCase). Pharmacological chaperones could potentially enhance GCase activity and treat GD and PD linked to mutations in the GBA gene (GBA-PD). Using ABX as pharmacological chaperone for macrophages derived from GD and GBA-PD patients we observed significantly enhanced GCase activity and decrease of HexSph concentration. For the first time was evaluated the effectiveness of chemical modifications of the previously described allosteric pharmacological chaperone.

Newborn screening of Gaucher diseases is important because of the development of treatment options that improve clinical outcome. The diagnosis of Gaucher disease relies on demonstration of deficient glucocerebrosidase enzyme activity in peripheral blood leukocytes.

The article is devoted to a rare pathology from the group of accumulation diseases with an autosomal recessive type of inheritance - type IIIA mucolipidosis in patients of the indigenous population of the Republic of Tyva. Ten children with this rare disease were examined. The main clinical symptoms of the disease are shown; 3 consecutive stages of diagnostic measures are presented, on the basis of which a new nucleotide substitution c. 3169T> G was found in all patients; Cys1057Gly in exon 16 of the GNPTAB gene. Revealed replacement was found in all patients in a homozygous state. It has been suggested that this option of replacement is a consequence of the effect of the ancestor and its carriage is characteristic only of persons of Tuvan nationality. For effective medical and genetic counseling of Tyva families, a population survey of the indigenous population of the Tuvan Republic on the carriage of the mutant GNPTAB gene is recommended.

MPS is a group of hereditary metabolic diseases associated with impaired glycosaminoglycan (GAG) metabolism, leading to multisystem damage of organs and tissues. Recently, a group of scientists revealed a new hereditary disease with an autosomal recessive inheritance type, belonging to the lysosomal disease group, clinically similar to MPS, with a mutation in the VPS33A gene, called mucopolysaccharidosis plus (MPS-PS) (OMIM # 617303), found in Yakut children, leading to early infant mortality, and also described simultaneously in 2 siblings from Turkey. The newly described c.1492C> T (p.Arg498Trp) mutation in the VPS33A gene is the cause of MPS-plus in both populations.

A clinical observation of porphyria is presented, in which the symptoms of the disease included vegetative syncope.

Mutations in the TRMU gene encoding the mitochondrial tRNA-specific 2-thiouridylase were found in infantile hepatopathy related to mitochondrial translation defect (OMIM# 613070). This condition is rare mitochondrial disorder with a life-threatening onset and with spontaneous remission, therefore a prompt diagnosis and treatment of these patients has importance in clinical practice. Here we describe a patient, with liver failure due to mutations in TRMU gene and compare with patients from literature.

Wilson’s disease is an autosomal recessive disease that develops as a result of the accumulation of copper in the organism when the ATP7B gene is damaged. The present study searched for mutations in this gene using massively parallel sequencing in patients with Wilson’s disease. For targeted enrichment of the regions of interest, a primer panel for PCR of long fragments was developed. In 6 patients out of 12 analyzed, pathogenic and probably pathogenic variants of the nucleotide sequence of the ATP7B gene were identified. The obtained results indicate that the developed method of targeted massively parallel sequencing allows efficient detection of mutations in the ATP7B gene.

The pyrosequencing is a reliable and robust technique for different variants of polymorphism (TA)5/6/7/8 verification in homo- and heterozygous state. The frequency of GS in outpatient patients was 24%. The application of «AmpliSens® Pyroscreen UGT1A1» kit in clinical practice.

Leber’s hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of “LHON plus” have been reported. The article presents an analysis of clinical case with the manifestation of neurological symptoms in adolescence.

The experience of determining the level of alpha-1 antitrypsin in serum in the population of the Republic of Sakha (Yakutia) is presented in the article.

The work presents a phylogenetic analysis of Helicobacter pylori strains circulating in Yakutia, according to three housekeeping genes of the atpA, mutY, ppa.