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Cystic fibrosis (CF) is a multisystem disease that affects the respiratory tract, gastrointestinal tract, liver, pancreas, salivary, sweat glands, reproductive system, caused by pathological variants of the CFTR gene located in the long arm of chromosome 7. Considering the fact that CF is the most common hereditary disease, transmitted in an autosomal recessive manner, threatening death and/or disability in case of late diagnosis, the study of population characteristics in different regions is important not only from an epidemiological, but also from a socio-economic point of view. High incidence of CF, the ability to identify the carrier of pathogenic CFTR gene variant, prenatal and preclinical diagnosis, adequate treatment and medical and social adaptation determine the need for organizing mass screening of newborns for this disease. Objective of this research is to evaluate the efficiency of neonatal screening for CF in RNO – Alania, to detect the frequency of its occurrence in the region, and to determine the molecular genetics features of CF in the population. A retrospective analysis of medical records of CF patients diagnosed before neonatal screening was carried out, as well as an analysis of the results of mass newborns screening for CF during 13 years from January 2007 to December 2019. Based on the analysis performed, it was found that the CF frequency in North Ossetia-Alania was 1:16369 live births, which is significantly lower than the average for Russia (1:9500).

The results of genetic and epidemiological study of monogenic hereditary diseases (HD) among children of the Karachay-Cherkess Republics are presented. The surveyed population comprised 410 368 individuals (Cherkessk and ten rural areas), including 90 739 children (22.11%). The examination was performed following the original protocol for genetic-epidemiological studies (developed by the Research Centre for Medical Genetics) making it possible to register not less than 3500 HD and syndromes. One hundred eighty-three nosological forms of HD (922 patients from 764 families) were registered in the child population, including 100 patients with AD (459 patients from 366 families), 60 patients with AR (372 patients from 326 families), and 23 patients with X-linked inheritance (91 patients from 72 families). The structure of diversity is determined, and frequent HDs are described in accordance with the main classification by organ and systemic types of disease: neurological, ophthalmic, genodermatoses, skeletal, hereditary syndromes, and other pathology. There were 55 frequent HDs (30.05%)—the number of patients in this group was 739 (80.15% of sick children). The load of AD, AR, and X-linked pathology for urban and rural child population was calculated. Differences in HD load were identified. On the basis of correlations between the load and FST, the causes of the observed differentiation of subpopulations were proposed.

The issue of point prevalence, cumulative prevalence (CP), and burden of rare hereditary diseases (RHD), comprising 72–80% of the group of rare diseases, is discussed in many reports and is an urgent problem, which is associated with the rapid progress of genetic technology, the identification of thousands of genes, and the resulting problems in society. This work provides an epidemiological analysis of the groups of the most common RHDs (autosomal dominant, autosomal recessive, and X-linked) and their point prevalence (PP) and describes the structure of RHD diversity by medical areas in 14 spatially remote populations of the European part of Russia. The total size of the examined population is about 4 million. A total of 554 clinical forms of RHDs in 10,265 patients were diagnosed. The CP for all RHDs per sample examined was 277.21/100,000 (1:361 people). It is worth noting that now is the time for characterizing the accumulated data on the point prevalence of RHDs, which will help to systematize our knowledge and allow us to develop a strategy of care for patients with RHDs. However, it is necessary to address the issues of changing current medical classifications and coding systems for nosological forms of RHDs, which have not kept pace with genetic advances.

Background: The problem of vitamin D deficiency is particularly relevant for the entire territory of Russia, since most parts of the country are located above the 42nd geographical latitude and the residents are therefore at risk of vitamin D deficiency. Despite the urgency of the problem, a comprehensive study of the molecular and genetic mechanisms and exogenous factors of vitamin D deficiency in children living in various geographical areas of the Russian Federation has not been conducted. Different variants in the loci of the genes responsible for the synthesis, hydroxylation, and transport of vitamin D (such as DHCR7, CYP2R1, CYP24A1, and GC), as well as VDR gene polymorphisms may also be associated with the risk of vitamin D deficiency. The aim of this study was to analyze the influence of exogenous factors on the blood levels of 25-hydroxyvitamin D (25(OH)D) in children of three regions of the Russian Federation, as well as the relationship of blood 25(OH)D levels with polymorphic variants of cytochrome P450 genes and VDR gene.Methods: We conducted blood 25(OH)D level analysis in 333 healthy children and adolescents in three regions located in different geographical zones of the Russian Federation. We studied the polymorphic variants c.1075A>C (I359L, rs1057910, CYP2C9*3) and c.430C>T (R144C, rs1799853, CYP2C9*2) in the CYP2C9 gene, c.1334T>C (M445T, rs4986910, CYP3A4*3), and CYP3A4*1B (c.-392C>T, rs2740574) in the CYP3A4 gene, 1846G>A, (rs3892097, CYP2D6*4) in the CYP2D6gene, TaqI (NM_000376.2: c.1056T>C; rs731236), FokI (NM_000376.2:c.2T>C; (rs2228570), and BsmI (NM_000376.2: c.1024+283G>A; rs1544410) in the VDR gene. We also analyzed the influence of exogenous factors on the level of 25(OH)D in children of the three study regions, as well as the relationship of the level of 25(OH)D with variants CYP2C9*2 (c.430C>T; R144C), CYP2C9*3 (c,1075A>C; I359L), CYP2D6*4 (1846G>A), CYP3A4*3 (c.1334T>C), and CYP3A4*1B (c.-392C>T) and rs731236, rs2228570 and rs1544410 in the VDR gene.Results: We found that the blood level of 25(OH)D depended on the geographical location and the number of sunny days per year. The average blood level of 25(OH)D in adolescent boys was statistically significantly lower than in girls of this age group. The level of 25(OH)D also significantly depended on the prophylactic dose of cholecalciferol administered to the subjects. In the study, it was shown that a dose of cholecalciferol ≥1,000 IU per day can achieve a normal level of 25(OH)D in healthy children. We found no statistically significant association between single-nucleotide polymorphic variants of cytochrome P450 genes (CYP2C9*3, CYP3A4*3, CYP2C9*2, CYP2D6*4, and CYP3A4*1B) and blood level of 25(OH)D in the subjects. We also did not find a relationship between the TaqI, FokI, and BsmI polymorphisms of the VDR gene and serum 25(OH)D concentration.Conclusion: Exogenous factors (time of year, place of residence, and prophylactic administration of cholecalciferol), as well as endogenous factors (age and sex), play a determining role in the development of vitamin D deficiency and insufficiency; in contrast to genetic factors—polymorphic variants of the genes of xenobiotic phase 1 enzymes (CYP2C9, CYP2C19, CYP2D6, and CYP3A4) and the VDR gene—which do not play such role. This study shows the need to create a diagnostic algorithm for Vitamin D deficiency based on the age, season of the year, and prophylactic dose of cholecalciferol.

The goal was to study the phenotypic manifestations of c.3844T>C (p.Trp1282Arg, W1282R) variant, a CF-causing mutation, in patients from the Russian Federation. Clinical manifestations and complications (the age at CF diagnosis, sweat test, pancreatic status, lung function, microbial infection, body mass index (BMI), the presence of meconium ileus (MI), diabetes, and severe liver disease) were compared in four groups: group 1—patients carrying c.3844T>C and severe class I or II variant in trans; group 2—3849+10kbC>T/F508del patients; group 3—F508del/F508del patients; and group 4—patients with W1282R and “mild” variant in trans. Based on the analyses, W1282R with class I or II variant in trans appears to cause at least as severe CF symptoms as F508del homozygotes as reflected in the early age of diagnosis, high sweat chloride concentration, insufficient pancreatic function, and low lung function, in contrast to 3849+10kbC-T/F508del compound heterozygotes having milder clinical phenotypes. The W1282R pathogenic variant is seemed to lead to severe disease phenotype with pancreatic insufficiency similarly to the F508del homozygous genotype.

The aim of this investigation was to analyse the register of cystic fibrosis (CF) patients of Central Federal District (CFD) of Russian Federation (RF) in 2017. The register of CF patients includes data on 3096 people from 81 regions-entities of RF. CF patients in CFD represent 30% of total amount of patients included in the register. The full data presents 9 regions. The data of the rest 9 regions is presented partially. There is a list of genetically, clinical and microbiological peculiarities in comparison with RF in general and, at the same time, with other districts of CFD. The difference between adult patients and average age of patients by areas of received treatment, laboratory and instrumental indicators. There are obvious differences in infection indicators of the same age groups, there is difference in provided therapy. The analysis of the register data will enable to optimize aid to CF patients in CFD, to take over the experience of regions with the best indicators and criteria of the progress of the disease.

Prevalence and allelic heterogeneity of hereditary diseases (HDs) could vary significantly in different human populations. Current knowledge of HDs distribution in populations is generally limited to either European data or analyses of isolated populations which were performed several decades ago. Thus, an acknowledgement of the HDs prevalence in different modern open populations is important. The study presents the results of a genetic epidemiological study of hereditary diseases (HDs) in the population of the Karachay-Cherkess Republic (KChR). Clinical screening of a population of 410,367 people for the identification of HDs was conducted. The population surveyed is represented by five major ethnic groups&mdash, Karachays, Russians, Circassians, Abazins, Nogais. The study of the populations was carried out in accordance with the proprietary protocol of genetic epidemiological examination designed to identify &gt, 3500 HDs easily diagnosed during clinical examination by qualified specialists specializing in the HDs. The protocol consists of the population genetic and medical genetic sections and is intended for comprehensive population analysis based on the data on different genetic systems, including the genes of HDs, DNA polymorphisms, demographic data collected during hospital-based survey. 8950 families (with 10,125 patients) with presumably the HDs were initially identified as a result of the survey and data collection through various sources of registration (from 1156 medical workers from 163 medical institutions). A diagnosis of hereditary pathology was established in 1849 patients (from 1295 families). Two hundred and thirty nosological forms were revealed (in 1857 patients from 1295 families). The total prevalence of HDs was 1:221. Differences between populations and ethnic groups were identified: 1:350 in Russians, 1:195 in Karachays, 1:199 in Circassians, 1:218 in Abazins, 1:135 in Nogais. Frequent diseases were determined, the presence of marked genetic heterogeneity was identified during the confirmatory DNA diagnosis. To explain the reasons for the differentiation of populations by load of HD, a correlation analysis was carried out between the FST (random inbreeding) in populations and HDs load values. This analysis showed genetic drift is probably one of the leading factors determining the differentiation of KChR populations by HDs load. For the first time, the size of the load and spectrum of HDs in the populations of the KChR are determined. We have demonstrated genetic drift to be one of the main factors of the population dynamics in studied population. A significant genetic heterogeneity of HDs, both allelic and locus, was revealed in KChR.

The clinical pictures of the disease of two Russian patients with cystic fibrosis with a rare nonsense variant c.831G>A (p.Trp277*) are described. The first case is a patient with the genotype comprising variant c.54-5940_273+10250del21kb (CFTRdele2,3), and the genotype of the second case included variant c.1521_1523delCTT (F508del). Patient 1, whose genotype had two class I genetic variants, revealed severe violations of CFTR synthesis based on the intestinal current measurements (ICM) and results obtained in the intestinal organoids. In both cases of patients with genetic variant c.831G>A, a severe course of cystic fibrosis was observed.

Summary Branchio-oculo-facial syndrome (BOFS, OMIM# 113620) is a rare autosomal dominant disorder characterised by branchial cleft sinus defects, ocular anomalies and facial dysmorphisms, including lip or palate cleft or pseudocleft, and is associated with mutations in the TFAP2A gene. Here, we performed clinical analysis and mutation diagnostics in seven BOFS patients in Russia. The phenotypic presentation of BOFS observed in three patients showed high heterogeneity, including variation in its main clinical manifestations (linear loci of cervical cutaneous aplasia, ocular anomalies and orofacial cleft). In certain other cases, isolated ocular anomalies, or an orofacial cleft with accessory BOFS symptoms, were observed. In five BOFS patients, conductive hearing loss was diagnosed. Direct sequencing of the coding region of the TFAP2A gene revealed missense mutations in four BOFS patients. One patient was observed to have a previously described mutation (p.Arg251Gly), while three patients from two families were found to have novel mutations: p.Arg213Ser and p.Val210Asp. These novel mutations were not present in healthy members of the same family and therefore should be classified as de novo.

Results: A yearly decline in FEV1 of approximately 1.1–4.1% has been described in the overall CF population, depending on the age group. In nmCF patients in the placebo arm of the study the relative decline in FEV1 from baseline to week 48 was 5.5% (SE 12.6). FVC in the placebo group declined by 2.5% (SE 0.7) over 48 weeks and FEF25%–75% declined by 3.9% (SE 1.8). Based on modified Fuchs’ criteria, the 48-week mean pulmonary exacerbation rate was 1.78 (SE 2.15) for nmCF patients. Conclusion: It is known that the natural history of CF is one of gradual pulmonary decline driven by infectious exacerbations. Data on nmCF patients followed for 48 weeks in the placebo group of a clinical trial showed a continuous decline in FEV1. The slope of the decline may indicate the severity of the phenotype. We will present data on underlying mutations and other baseline demographics. Analysis of longer-term follow-up data will provide further insights in the natural history of nmCF.

Objectives A national newborn screening (NBS) program for cystic fibrosis (CF) was introduced all over Russia in January 2007. Currently, this is the main method of CF diagnosis in the country and from 140 to 190 CF newborns are diagnosed per year. In the Moscow region NBS is carried out from June 2006. In total 134 CF patients were identified (the end 2014). Methods From the Moscow region CF Patients Register we analyzed the data of all diagnosed CF patients under 18 years old in two different periods: from 1999 to 2005 (before the introduction of NBS in Moscow – Group I) and from 2007 to 2013 (Group II). Results Before the NBS program CF was diagnosed in 83 patients. In the period 2007–2013 CF was diagnosed in 228 CF patients. The average age at diagnosis in Group I was 4.5 years (30% before 12 months), and in Group II – 1.8 years (74% before 12 months). The average age of patients at CF diagnosis in the positive NBS group was 2.3 months, in the infants with false-negative NBS results – 23 months. In Group I meconium ileus (MI) was diagnosed in 5 children (6%), and in Group II – in 27 children (12%). We assume there were much more cases of CF under-diagnosis in MI newborns in Moscow region before 2007. MI patients in Group I were diagnosed as having CF at the age of 1.4 years, and in Group II – 1.7 months. Conclusion Our findings demonstrate both the effectiveness of NBS and a greater awareness of CF nosology among physicians. At the same time, underdiagnosed CF before NBS program, false-negative NBS and sweat testing results, as well as a number of CF health care organization problems in Moscow still influence the diagnosis age of new CF patients.

Analysis of the diversity of monogenic hereditary diseases in eight raions (districts) of Rostov oblast (region) of Russia (Tsimlyansk, Volgodonskoi, Tselina, Egorlykskaya, Millerovo, Tarasovskaya, Rodionovo-Nesvetaiskaya, and Matveevo-Kurgan raions) has been summarized. The total sample size was 320925 subjects. The spectrum of hereditary diseases detected in the eight districts comprises 187 diseases, including 99 autosomal dominant (AD), 72 autosomal recessive (AR), and 16 X-linked diseases. The mean prevalence rate of each disease in the total population has been calculated. Accumulation of individual diseases in different regions of Rostov oblast has been calculated; the disease accumulation has been compared with that in some populations of Russia examined earlier. Cluster analysis using the data on the frequencies of genes of hereditary diseases has shown the gene geographic position of the Rostov oblast population among the following ethnic populations of Russia: Russians (Kostroma, Kirov, and Rostov oblasts and Krasnodar krai), Chuvashes (Chuvashia), Adygeans (Adygea), Maris (Marii El), and Udmurts (Udmurtia).