The genetic structure of Karachay population has been studied on the basis of analysis of ten autosomal DNA markers (diallelic and multiallelic) of the nuclear genome: CCR5∆32, ID/АСЕ, D7S23(KM19), STR/THOI, STR/FABP2, STR/IVS6aGATT(CFTR), VNTR/PAH, VNTR/DAT1, VNTR/NOS3, VNTR/APOB. The total number of the sample comprises 485 individuals who are residents of four Karachay regions: Karachaevsky, Prikubansky, Malokarachayevsky, Ust-Dzhegutinsky, and the city of Cherkessk, the capital of the Karachay-Cherkess Republic. Analysis of allele’s frequency of autosomal DNA markers in Karachay geographic subgroups shows considerable genetic differentiation between them. The highest level of genetic diversity for Karachay people on the diallelic system is set at the locus ID/АСЕ, Hobs = 0.513, and on the multiallelic system is at the locus STR/THOI, Hobs = 0.792. The average value of the observed heterozygosity per locus is 0.466, varying from 0.441 in Ust-Dzhegutinsky region to 0.503 in Cherkessk. The level of genetic differences between Karachay groups (FST = 0.007) is inside the variance defined in the previously studied peoples: Mari (FST = 0.0024), Udmurt (FST = 0.0048), Chuvash (FST = 0.006), Tatars (FST = 0.0075), and Bashkir (FST = 0.008).

This text is a continuation of a review of international studies and guidelines/recommendations for primary prevention of cystic fibrosis (CF). This section reviews the selection of pathogenic variants for different CF mutation carrier screening programmes to form panels, taking into account the geographical and ethnic characteristics of the couples being screened, describes the monitoring of couples at intermediate risk of carrier, presents the relationship between carrier screening and neonatal screening, highlights the importance of timely information, including medical and genetic counselling for stakeholders, taking into account the psychosocial status. Separately, we present studies that have found a reduction in the rate of CF births in France, Italy and Israel after the introduction of CF carrier screening.

Aim: genetic epidemiological study of hereditary eye diseases in various populations of the Russian Federation and comparative analysis of these findings. Patients and Methods: the sample included 12 ethnic groups from 14 regions of European Russia. The entire population irrespective of gender or age was examined. To confirm a certain type of inheritance of diseases from heterogeneous groups, the material was subjected to the multicomponent analysis used in multiple family registration. The rate of segregation was evaluated using the Weinberg proband method. Molecular genetic tests (Sanger sequencing, MLPA, AFLP, RFLP, whole exome sequencing) were applied. To identify the cases of hereditary disease accumulation in individual populations and/or ethnic groups, the prevalence of certain diseases in this population was calculated using F-distribution to compare the samples of rare diseases. Results: more than 46,000 patients and their relatives with presumably hereditary conditions were examined and data were collected. 554 clinically diverse hereditary diseases in 9,979 individuals were identified. Isolated hereditary eye disease (60 clinical variants) was identifie in 1,407 patients (14.56%). The mean prevalence of isolated hereditary eye disease was 1:2,272 (or 44.01 per 100,000). When assessing patterns of nosological spectrum and prevalence of isolated hereditary eye disease in each population/ethnic group using principal component analysis, 2 clusters were isolated. The first cluster includes 6 Russian populations and the second cluster includes 5 ethnic Volga Region groups, which are more similar to Russian populations than the North Caucasus people. In general, 57 hereditary syndromes (affecting anterior and posterior eye segments) in 1,051 patients were discovered. The mean prevalence of syndromic hereditary eye disease was 1:3,040 (or 32.89 per 100,000). Keywords: ophthalmogenetics, genetic epidemiological study, spectrum, ethnic group, type of inheritance, segregation, accumulation, isolated and syndromic hereditary eye diseases, prevalence, retinal degeneration. For citation: Kadyshev V.V., Ginter E.K., Kutsev S.I. et al. Epidemiology of hereditary eye disease in the populations of Russian Federation. Russian Journal of Clinical Ophthalmology. 2022;22(2):69–79 (in Russ.). DOI: 10.32364/2311-7729-2022-22-2-69-79.

Патогенные варианты в гене GJB2 являются наиболее частой молекулярной причиной несиндромальной аутосомно рецессивной нейросенсорной тугоухости типа 1 (DFNB1). В работе оценен спектр генетических вариантов и доли GJB2-ассоциированной тугоухости у пациентов с наследственными несиндромальными нарушениями слуха в популяции осетин из Республики Северная Осетия-Алания (РСО-Алания). Проведено секвенирование по Сэнгеру экзонов 1 и 2 гена GJB2 с последующим анализом вариации числа копий локусов путём мультиплексной лигаза-зависимой амплификации зондов (MLPA). Исследование включало 83 пациента с наследственной несиндромальной нейросенсорной тугоухостью из 74 неродственных семей из популяции осетин РСО-Алания. Причина несиндромальной нейросенсорнй тугоухости у осетин в РСО-Алания, обусловленная патогенными вариантами гена GJB2, подтверждена в 26,8% случаев. Два генетических варианта GJB2 (GJB2(NM_004004.6):c.358_360del (p.Glu120del) - 54,2% и GJB2(NM_004004.6):c.35del (p.Gly12ValfsTer2) - 37,5%) составляют 91,7% патогенных аллелей гена GJB2. Pathogenic variants in the GJB2 gene are the most common molecular cause of nonsyndromic autosomal recessive sensorineural hearing loss type 1 (DFNB1). The aim of the work was to evaluate the spectrum of genetic variants and the proportion of GJB2-associated hearing loss in patients with hereditary non-syndromic hearing disorders in the Ossetian population from the Republic of North Ossetia-Alania. Sanger sequencing of 1 and 2 exons of the GJB2 gene, followed by analysis of the variation in the number of copies of loci by multiplex ligase-dependent amplification (MLPA) was carried out. The study was conducted on a sample of 83 patients with hereditary nonsyndromic sensorineural hearing loss from 74 unrelated families from the population of Ossetians of the Republic of North Ossetia-Alania (RSO-Alania). The cause of nonsyndromic sensorineural hearing loss in Ossetians in the RSO-Alania, due to pathogenic variants of the GJB2 gene, was confirmed in 26.8% of patients. Two genetic variants (GJB2(NM_004004.6):c.358_360del (p.Glu120del)) - 54.2% и GJB2(NM_004004.6):c.35del (p.Gly12ValfsTer2) - 37.5%) account for 91.7% of pathogenic alleles of the GJB2 gene in Ossetian patients.

На материале ряда различных популяций России показано, что изменение индекса эндогамии во второй половине ХХ в. не носит глобального характера. Популяции с более низким уровнем индекса эндогамии существенно не меняют эндогамность во времени, сохраняя большую миграционную активность населения. Тенденция сохранения эндогамности популяций во времени характерна и для групп регионов со средними и высокими значениями эндогамности. В городах отмечается рост индекса эндогамии, в сельской местности – его снижение.

Приведены результаты медико-генетического обследования населения трех районов Республики Северная Осетия-Алания (РСОА) - Ардонского, Правобережного, Кировского, общей численностью 116897 человек. Обследование населения изученных районов проведено тотально (независимо от национальности и поло-возрастной структуры) в соответствии с протоколом генетико-эпидемиологических исследований, разработанным в ФГБНУ «МГНЦ». После проведенного сегрегационного анализа рассчитаны значения отягощенности (на 1000 человек) основными типами менделирующей патологии (АД, АР и Х-сц.) населения трех районов Республики. Значения груза АД наследственной патологии у городского населения составили 3,62 в Ардонском, 1,86 в Правобережном и 2,10 в Кировском районах. В сельской местности груз АД патологии оказался существенно выше: 5,33 (Ардонский район), 3,23 (Правобережный район), 4,13 (Кировский район). Груз АР патологии в городских популяциях составил 1,17, 1,59 и 2,82 (Ардонский, Правобережный и Кировский районы, соответственно). В сельских популяциях распространенность АР патологии составила 1,81 (Ардонский район), 2,38 (Правобережный район) и 3,10 (Кировский район). Значения груза Х-сц. патологии варьировали от 0,43 в городской популяции Правобережного района до 1,29 в городской популяции Кировского района. Характеристики груза наследственных болезней рассматриваемых районов РСОА, близки к тем, которые были получены для населения некоторых районов Республик Волго-Уральского региона и Северного Кавказа. В русских популяциях европейской части России значения груза наследственной патологии существенно ниже. The results of medical genetic study of three Districts of the Republic of North Ossetia-Alania (RNOA) - Ardonsky, Pravoberezhny and Kirovsky, with a total number of 116897 people, are reviewed. A survey of the investigated Districts was conducted totally (regardless of nationality, age and gender structure), in accordance with the Protocol of genetic-epidemiological studies - development of the Research Centre for Medical Genetics. After the segregation analysis, we calculated the load of the main types of Mendelian hereditary pathology (AD, AR and X-linked) for the entire population of three regions of the Republic. Segregation analysis demonstrated good agreement between the observed and expected segregation frequencies for both AR and AD diseases. The load (per 1000 individuals) of Mendelian hereditary pathology (autosomal dominant, autosomal recessive and X-linked) was estimated. In the urban populations the load of autosomal dominant pathology was 3.62 in Ardonsky, 1.86 in Pravoberezhny and 2.10 in Kirovsky District; in the rural populations the load of autosomal dominant pathology was substantially higher: 5.33 (Ardonsky), 3.23 (Pravoberezhny), 4.13 (Kirovsky). The prevalence rates of autosomal recessive disorders in urban populations were per 1.17 in Ardonsky, 1.59 in Pravoberezhny and 2.82 in Kirovsky District. In the rural populations of these Districts they were 1.81 in Ardonsky, 2.38 in Pravoberezhny, 3.10 in Kirovsky District. The values of the load of X-linked pathology varied from 0.43 in the urban population of the Pravoberezhny District to 1.29 in the urban population of the Kirov District. Characteristics of the load of hereditary diseases of the considered Districts of RNOA are close to those that were obtained for the population of some areas of the Republic of the Volga-Ural region and the North Caucasus. In the Russian populations of the European part of Russia the values of load of hereditary pathology are significantly lower.

Проведен анализ результатов генетико-эпидемиологических исследований наследственных болезней (НБ) в 14 регионах европейской части России, Юга России, Северного Кавказа, Волго-Уральского региона с суммарной численностью обследованного населения около 4 млн чел. Изучены пространственная изменчивость и генетическая гетерогенность НБ у населения различных регионов и в полиэтнических популяциях РФ. Выделены частые НБ, характерные как для всего населения конкретных регионов, так и заболевания, специфичные для отдельных этносов. Выявлена гетерогенность НБ в популяциях и этносах, как аллельная, так и локусная. Зарегистрированы ранее не описанные НБ, эндемичные для конкретных этносов. Показано, что в популяциях с различной этнической экстракцией каждый народ в своем генофонде сохранил специфический спектр, распространенность и генетическую природу НБ. Проведенный анализ позволил подойти к решению фундаментальной проблемы медицинской генетики - эволюции НБ в различных популяциях и этнических группах. 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.

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—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 >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.

solution to determine the magnitude of FSK-induced short-circuit current (I sc ) change and its response to 0.3 μM VX770.Results: AUC was significantly improved: 3 ± 1,3 fold following treatment with 0,128 μM FSK + 3 μM VX770for 180 minutes comparing to vehicle (FSK + DMSO) (n = 4, p < 0.01).The I sc response to 10 μM FSK was 19,78 with reference WT values of 114,5 (n = 2), and VX770 addition increased the value to 27,11 μA/cm 2 .Conclusions: Rectal organoids carrying c.1584 + 18672bpA > G and 2183AA > G CFTR variants present with a residual CFTR function as measured by both FIS and I sc assays and VX770 treatment improved it, suggesting a potential clinical benefit for patients with this CFTR genotype.

The generalized results of the genetic and epidemiological study of the genetic structure of various ethnic groups of the Karachay-Cherkess Republic (KChR) through various genetic systems are presented: by the genes causing AD, AR, and X-linked hereditary diseases and by nonbiological parameters estimated by the methods of population statistics (random inbreeding FST, Malécot’s isolation-by-distance parameters, migration index, and Crow index and its components). The total size of the investigated population was 410 367 individuals (city of Cherkessk, Ust-Dzhegutinsky, Karachayevsky, Malokarachayevsky, Prikubansky, Khabezsky, Nogaysky, Adyge-Khablsky, Urupsky, and Zelenchuksky districts). On the basis of the study of correlations between different characteristics of the population genetic structure, it is assumed that the main cause of genetic differentiation of KChR subpopulations in terms of diversity and load of hereditary diseases (AD, AR, and X-linked) is genetic drift and migration under decreased influence of natural selection and mutational process.

Rationale: Cystic fibrosis (CF; OMIM 219700) is a common hereditary disease caused by mutations in the CFTR gene (OMIM 602421). The distribution and frequencies of the CFTR gene mutations vary considerably between countries and ethnic groups. By now about 11% alleles of the CFTR gene remain unidentified after testing for frequent mutations in the Russian patients. A full determination of the mutation spectrum in the CFTR gene is necessary to optimize medical and genetic assistance to the population and to implement the achievements of targeted therapy in the treatment of CF patients.Materials and methods: The sample included 121 Russian CF patients, in whom testing for 34 routinely analyzed mutations did not identify one (n = 107) or both (n = 14) mutant alleles. Assessment of the coding sequence of the CFTR gene, including the regions of exon-intron junctions, 5’- and 3’-untranslated regions was performed by the Sanger sequencing method; in addition, the search for large rearrangements was conducted by the multiplex ligation-dependent probe amplification (MLPA) method.Results: In addition to the previously identified, 88 more variants were determined, including 28 missense mutations, 15 nonsense mutations, 18 frameshift mutations (14 deletions, 4 insertions), 14 splicing mutations, 1 in-frame insertion, 1 in-frame deletion, 1 in/del mutation, and 10 large rearrangements (7 deletions, 3 duplications). Twenty three (23) novel variants were sequenced. Four (4) complex mutant alleles were found. Sixty (60) variants are found once each. One hundred and thirty four (134) of 135 tested mutant alleles were identified.Conclusion: Consequent use of the sequencing and MLPA methods has allowed for identification of a high proportion of the tested mutant alleles in CF patients from Russia (134/135, > 99%), to detect a significant diversity of the CFTR mutation spectrum (88 additional variants, 32 of them novel), a number of repeated mutations (c.2353C>T, c.1240_1244delCAAAA, c.1766+1G>A and c.3929G>A) encountered in 5 or more unrelated patients, which could be included in the panel of routinely analyzed variants in the Russian CF patients; and a high proportion of large rearrangements of the CFTR gene.

In order to optimize economic and organizational technologies for the provision of medical care to the population and to increase the effectiveness of preventive programs, an analysis of the accumulated morbidity and prevalence of monogenic hereditary diseases (MHDs) has been carried out in 13 federal subjects of the Russian Federation representing 11 ethnic groups: Russians of 6 regions, Tatars, Maris, Chuvashs, Bashkirs, Udmurts, Abazins, Adygeans, Nogays, Circassians and Karachays. The study of the population was carried out according to the developed protocol of complex genetic and epidemiological studies in the Research Center for Medical Genetics, which remains unchanged throughout the study. Here we have studied the structure of the genetic load and diversity of MHDs depending on the prevalence of diseases and in accordance with the classification by organ and system types of disease: neurological, ophthalmological, genodermatosis, skeletal, hereditary syndromes, and other hereditary pathology (metabolic hereditary diseases, disorders of blood, hearing, etc.). It is shown that the maximum number of patients (61.81%) falls in the group of frequent forms of MHDs, which differ by federal subjects / ethnic groups of the Russian Federation. There are frequent forms of MHDs for all populations, and "specific" forms for particular federal subjects of the Russian Federation/ethnic groups. Only for a small group of hereditary diseases there is treatment. Most of the detected diseases-psychiatric, neurological, hematological, and hereditary syndromes-significantly reduce life expectancy. Hereditary diseases of the skeleton, eyes, ears and metabolism affect the quality of life, adaptation in society and public health. On average, 65% of patients are diagnosed with MHDs for the first time. This situation implies changes in medical thinking, changes in education and development of both common for all regions and specific prevention programs. Thus, fundamental research in medicine can improve the quality of medical services and contribute to the improvement of public health.

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 F-ST, the causes of the observed differentiation of subpopulations were proposed.

Детская клиническая больница № 1, ярославль 150003, Российская Федерация 36 Клиническая больница № 2, ярославль 150010, Российская Федерация Цель исследования.Изучить особенности и разнообразие спектра патогенных генетических вариантов гена CFTR (ABCC7) у российских пациентов с МВ, представленных в Регистре больных муковисцидозом (МВ) Российской Федерации (РФ) 2017г.Материал и методы.Проанализированы результаты генотипирования, включавшего анализ частых патогенных генетических вариантов, секвенирование кодирующей последовательности, поиск генных перестроек гена CFTR, 3096 больных из 81 региона-субъекта Российской Федерации, представленных в Регистре больных МВ в РФ 2017 г.Результаты.Выявлено 196 патогенных генетических вариантов гена CFTR.Суммарная доля 11 генетических вариантов c.1521_1523delCTT (F508del), c.54-5940_273+10250del21kb (CFTRdele2,3), c.274G>A (E92K), c.2012delT (2143delT), c.3718-2477C>T (3849+10kbC->T), c.3846G>A (W1282X), c.2052_2053insA (2184insA), c.1545_1546delTA (1677delTA), c.3909C>G (N1303K), c.1624G>T (G542X), c.413_415dupTAC (L138ins) составляет 75,6 %. 102 редких вариантов обнаружены однократно, 29 -дважды.Как в спектре, так и по частоте у пациентов в РФ преобладают варианты, приводящие к серьезным нарушениям функции белка CFTR (I, II, III классы).44 генетических варианта не внесены в базы CFTR1 и CFTR2.Заключение.На основании данных Регистра 2017 года определены спектр и относительные частоты патогенных вариантов последовательности гена CFTR у российских больных МВ; описано их распределение в зависимости от класса и типа.Выявлены генетические варианты, ранее не описанные в базах CFTR1 и CFTR2.Полученные результаты могут использоваться для оптимизации генетического консультирования и клинической работы с семьями, отягощенными МВ, а также для дальнейших исследований патогенетической значимости ранее не описанных генетических вариантов гена CFTR.

Desmoid-type fibromatosis (DF) is a rare mesenchymal tumor occurring in only 2 to 4 people per 1,000,000 population a year. Desmoid tumors are either seen sporadically or in individuals with familial adenomatous polyposis (FAP). The etiology of sporadic DF is uncertain. The aim of this study was to estimate the potential significance of germline mutations in the APC gene in patients with sporadic DF. APC exons were amplified, studied using conformation sensitive gel electrophoresis and then Sanger-sequenced. The obtained data were processed in Statistica 10. Mutations were detected in 6 (12%) of 51 participants with sporadic DF. Those 6 patients shared a typical DF phenotype characterized by early age of onset (5.8 years on average, in contrast to the patients without APC mutations, who developed DF at 19 years of age; p = 0.02), severe clinical course, multifocal localization on the trunk, and poor prognosis. All of the detected APC mutations were localized to the 3'-end of the gene. For the purpose of comparison, we analyzed a sample of 12 patients with FAP-associated DF. Of those patients, 6 carried mutations in the APC gene. In the analyzed sample, the patients with FAP and the mutant APC gene developed DF at older age (35 years) than the patients with sporadic DF (p = 0.004) and their tumors were not multifocal. This means that sporadic and FAP-associated desmoids have different phenotypes in patients with APC mutations. Patients with sporadic tumors have mutations at the 3'-end of the APC gene more often than individuals with FAP-associated DF. To our knowledge, this is the first study to characterize the subtype of sporadic desmoid fibromatosis phenotypically determined by germline mutations in the APC gene.