[Main methodological approaches to the identification and diagnosis of monogenic hereditary diseases and problems in the organization of medical care and unified preventive programs].

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.

Spectrum of CFTR mutations in Chechen cystic fibrosis patients: high frequency of c.1545_1546delTA (p.Tyr515X; 1677delTA) and c.274G>A (p.Glu92Lys, E92K) mutations in North Caucasus.

BACKGROUND: Cystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease caused by pathogenic variants (henceforward mutations) in the cystic fibrosis transmembrane conductance regulator gene (CFTR). The spectrum and frequencies of CFTR mutations vary among different populations. Characterization of the specific distribution of CFTR mutations can be used to optimize genetic counseling, foster reproductive choices, and facilitate the introduction of mutation-specific therapies. Chechens are a distinct Caucasian ethnic group of the Nakh peoples that originated from the North Caucasus. Chechens are one of the oldest ethnic groups in the Caucasus, the sixth largest ethnic group in the Russian Federation (RF), and constitute the majority population of the Chechen Republic (Chechnya). The spectrum of CFTR mutations in a representative cohort of Chechen CF patients and healthy individuals was analyzed. METHODS: Molecular genetic analysis of 34 CFTR mutations (representing approx. 80-85% of mutations in multiethnic CF populations of the RF) was performed in 32 CF patients from 31 unrelated Chechen families living in Chechnya. One hundred randomly chosen healthy Chechens were analyzed for the 15 most common "Russian" mutations. The clinical symptoms in Chechen CF patients with different CFTR genotypes were investigated. RESULTS: High frequencies of c.1545_1546delTA (p.Tyr515X; 1677delTA) (52 out of 64 CFTR alleles tested; 81.3%) and c.274G > A (p.Glu92Lys, E92K) (8/64, 12.5%) mutations were found. Twenty patients were homozygous for the c.1545_1546delTA mutation, and eight were compound heterozygous for the c.1545_1546delTA and c.274G > A mutations. Three carriers of the c.1545_1546delTA mutation were also found in the cohort of 100 apparently healthy Chechens (frequency - 0.015). The c.1545_1546delTA and c.274G > A mutations are linked to the same haplotype (22-7-16-13) of intragenic Short Tandem Repeat markers, i.e., IVS1CA, IVS6aGATT, IVS8CA, and IVS17bCA. CONCLUSIONS: The distribution of CFTR mutations in the Chechen CF population is unique regarding the high frequency of mutations c.1545_1546delTA and c.274G > A (more than 90% of the mutant alleles). The c.274G > A mutation is associated with a less severe course of CF than that observed in c.1545_1546delTA homozygotes. Testing for these two variants can be proposed as the first step of CF DNA diagnosis in the Chechen population.

Expression Profiles of Genes-Potential Therapy Targets-and Their Relationship to Survival in Renal Cell Carcinoma.

The main mechanisms of pathogenesis of clear cell renal cell carcinoma (CCRCC) are realized through the PI3K-AKT-mTOR and Ras-RAF-ERK signaling pathways. Targeted therapy is directed primarily at the genes and their encoded products that are components of these pathways. The levels of expression and coexpression of target genes were determined, and the difference in the functioning of the genes of one of the two major signaling pathways in tumors of CCRCC patients with different life duration (more and less than 3.5 years) and the relationship of the VEGFA gene expression level with the life duration was revealed.

Molecular analysis of patients with aniridia in Russian Federation broadens the spectrum of PAX6 mutations.

Congenital aniridia is a severe autosomal dominant congenital panocular disorder, mainly associated with pathogenic variants in the PAX6 gene. The objective of the study was to investigate the mutational and clinical spectra of congenital aniridia in a cohort of 117 patients from Russia. Each patient underwent detailed ophthalmological examination. From 91 unrelated families, 110 patients were diagnosed with congenital aniridia and 7 with WAGR syndrome (Wilms tumor, Aniridia, Genitourinary anomalies, and mental Retardation syndrome). The clinical presentation in aniridia patients varied from the complete bilateral absence of the iris (75.5%) to partial aniridia or iris hypoplasia (24.5%). Additional ocular abnormalities were consistent with previous reports. In our cohort, we saw a previously not described high percentage of patients (45%) who showed non-ocular phenotypes. Prevalence of deletions coherent with WAGR syndrome appeared to be 19.4% out of sporadic patients. Among the other aniridia cases, PAX6 deletions were identified in 18 probands, and small intragenic changes were detected in 58 probands with 27 of these mutations being novel and 21 previously reported. In 3 families mosaic mutation was transmitted from a subtly affected parent. Therefore, PAX6 mutations explained 96.7% of aniridia phenotypes in this study with only 3 of 91 probands lacking pathogenic variants in the gene.

[Marriage and Migratory Characteristic of Circassians (Late 20th Century)].

This paper analyzes 2052 marriage records for 1990-2000 in the Khabezsky district of Karachay-Cherkessia. The main marriage and migration characteristics of Circassians are studied: index of endogamy, ethnic mar- riage assortativity, intensity of metisation, and Malecot's parameters of isolation by distance.

Whole exome sequencing links dental tumor to an autosomal-dominant mutation in ANO5 gene associated with gnathodiaphyseal dysplasia and muscle dystrophies.

Tumors of the jaws may represent different human disorders and frequently associate with pathologic bone fractures. In this report, we analyzed two affected siblings from a family of Russian origin, with a history of dental tumors of the jaws, in correspondence to original clinical diagnosis of cementoma consistent with gigantiform cementoma (GC, OMIM: 137575). Whole exome sequencing revealed the heterozygous missense mutation c.1067G > A (p.Cys356Tyr) in ANO5 gene in these patients. To date, autosomal-dominant mutations have been described in the ANO5 gene for gnathodiaphyseal dysplasia (GDD, OMIM: 166260), and multiple recessive mutations have been described in the gene for muscle dystrophies (OMIM: 613319, 611307); the same amino acid (Cys) at the position 356 is mutated in GDD. These genetic data and similar clinical phenotypes demonstrate that the GC and GDD likely represent the same type of bone pathology. Our data illustrate the significance of mutations in single amino-acid position for particular bone tissue pathology. Modifying role of genetic variations in another gene on the severity of the monogenic trait pathology is also suggested. Finally, we propose the model explaining the tissue-specific manifestation of clinically distant bone and muscle diseases linked to mutations in one gene.

High prevalence of W1282x mutation in cystic fibrosis patients from Karachay-Cherkessia.

Cystic fibrosis (CF; OMIM #219700) is a common autosomal recessive disease. The spectrum and frequency of CFTR mutations vary significantly in different populations and ethnic groups. A genetic epidemiological study was conducted in the indigenous ethnic group of people known as the Karachais. They live in the Republic of Karachay-Cherkessia, which lies in the northwest of Russia's North Caucasus region. Karachai's are Turkic-speaking and consist of 194 thousand people (approximately 40% of the population of the Republic). Molecular genetic analysis was performed in 10 unrelated Karachai families with CF patients from three districts in the Republic. A high frequency of W1282X mutation was found (18 of 20 mutant alleles): eight patients were homozygous for the W1282X mutation, and two were compound heterozygous (the second alleles were R1066C and R709X). Analysis for 13 common CF mutations in the sample of 142 healthy Karachais identified two 1677delTA and two W1282X mutation carriers. Thus, the most common CFTR mutation, F508del, was not detected among the CF patients or in healthy Karachais. The most frequent mutation among Karachai patients is W1282X (90%). Its frequency in healthy Karachais is approximately 0.007. Haplotype analysis using the CFTR intragene DNA markers IVS1CA, IVS6aGATT, IVS8CA and IVS17bCA showed that the origins of the W1282X mutation in Karachay-Cherkessia and the Eastern European part of Russia are different.

[Advance of genetics and genomics in neurology].

Studies of genomic background of neurological disorders are very actual in view of their high population prevalence, severe course, serious impact on patients' disability and progressive mental and physical de-adaptation. In the paper, problems of genetic heterogeneity of hereditary neurological disorders and character of the respective genetic burden in the regions of Russian Federation are discussed in detail, a 'dynamic' type of mutations (increase in number of microsatellite repeats copies) attributable to many neurodegenerative diseases is analyzed, and achievements of Russian researchers in the identification of genes for hereditary neurological disorders and in the realization of pilot protocols of gene therapy are presented. Problems related to studies of genetic predisposition to common multifactorial diseases of the nervous system are discussed.

[Genetic epidemiological study of monogenic hereditary diseases in the Republic of Tatarstan: population dynamic factors determining the differentiation of the load of hereditary diseases in five districts].

A genetic epidemiological study has been performed in five districts of the Republic of Tatarstan, Russia: Arsky, Atninsky, Kukmorsky, Buinsky and Drozhzhanovsky raions. The total size of the population surveyed is 188 397 people. Tatars accounted for 77.13% of the population analyzed (145466 people) and were represented by two main ethnic groups: Kazan Tatars and Mishars. The medical genetic study encompassed the total population of the districts, irrespective of ethnicity, and was carried out according to the standard protocol developed in the Laboratory of Genetic Epidemiology of the Research Center for Medical Genetics of the Russian Academy of Medical Sciences. After segregation analysis, the prevalence rates of the main types of monogenic hereditary disorders (MHDs), i.e., autosomal dominant (AD), autosomal recessive (AR), and X-linked diseases, have been calculated for the total population of the five districts and for Tatars alone. The prevalence rates ofAD, AR, and X-linked diseases considerably vary in different subpopulations. The largest difference in the MHD prevalence rate has been found between the rural and urban populations. The overall prevalence rate of MHDs was one patient per 293 urban residents and populations and one patient per 134 rural residents, with a wide variation between subpopulations, from 1 : 83 people in the rural population of Atninsky raion to 1: 351 people in the town of Kukmor. Comparison of the MHD prevalence rate in Tatars with those in populations surveyed earlier has shown that the characteristics of the load of MHDs in the Tatar population are similar to those in some districts of the republics of Bashkortostan, Udmurtia, Mari El, and Chuvachia. In Russian populations of European Russia, the MHD prevalence rates are substantially lower. Correlation analysis has shown high (r = 0.5-0.9) significant correlations between the local inbreeding (a), the im index, the random inbreeding (F(ST)), and the AD and AR prevalence rates in the Tatar population. This analysis has demonstrated that genetic drift is the main population dynamic factor determining the MHD load in the Tatar population.

[Organization of medical genetic service in Russia].

Short history of the development of medical genetic service in Russia from the 1960s till now is described. Analysis of many orders of the Ministry of Health of USSR and Russia was performed which shows how separate components of the service were designed and integrated into the efficacious genetic counseling system. All of them were supported by educational programs. The important contribution made by professor Nikolai Bochkov to the creation of genetic service in Russia especially at the early stages is underlined.

[Genetic epidemiological study of Bashkortostan Republic: the effect of genetic structure of population on the load of monogenic hereditary diseases].

Here we present the data obtained during medical genetic examination of the population of five districts of Bashkortostan Republic (Burzyanskii, Baimakskii, Abzelilovskii, Salavatskii, and Arkhangelskii) populated with 168050 persons including 135748 Bashkirs. The study involved all the population of the districts including each ethnic group and was conducted according to standard protocol developed in the Laboratory of Genetic Epidemiology, Medical Genetic Research Center, Russian Academy of Medical Sciences. Based on segregation analysis, the values of prevalence rates of the major types of Mendelian pathology (AD, AR, and X- linked diseases) was calculated in five regions of the Republic as well as for Bashkirs alone. Significant differences in the prevalence rates of AD and AR pathologies between individual districts, in particular upon division in rural and urban population, was observed. The prevalence rates comparison of monogenic hereditary pathology among Bashkirs compared to other previously examined populations have shown that the patterns of the hereditary disease load in the inspected districts of Bashkortostan were similar to that observed in the population of some districts in Udmurtia, Marii El and Chuvashiya. Russian European populations have shown significantly lower load of hereditary diseases. Correlation analysis of local inbreeding, endogamy and prevalence rates of AD and AR pathologies has shown that development of hereditary diseases load is significantly affected by gene drift.

[Genetic epidemiological study of Bashkortostan Republic: the diversity of monogenic hereditary diseases in five districts].

The diversity of monogenic hereditary diseases (HDs) (autosomal dominant (AD), autosomal recessive (AR), and X-linked diseases) has been studied in five districts of Bashkortostan Republic: Burzyanskii, Abzelilovskii, Baimak, Salavatskii, and Arkhangel'skoe raions. The spectrum of HDs comprised 144 diseases, including 83, 48, and 13 Ad, AR, and X-linked diseases. Most of them were found earlier during studies in ten other regions of Russia (Kirov, Kostroma, Tver', Bryansk, and Rostov oblasts, and Krasnodar krai, and the republics of Adygea, Marii El, Udmurtia, and Chuvashia). Foci of local accumulation of some AD, AR, and X-linked diseases have been found in individual districts. Data on the gene frequencies for the HDs have been used for cluster analysis, which has shown the gene geographic position of Bashkirs among nine ethnic populations of Russia: Russians (Kostroma, Kirov, and Rostov oblasts and Krasnodar krai), Chuvashes (Chuvashia), Adygeans (Adygea), Maris (Marii El), Udmurts (Udmurtia), and Bashkirs (Bashkortostan).

Laminopathies in Russian families.

Mutations in LMNA gene produce a wide spectrum of disorders called laminopathies. In this article, the first cases of laminopathies from Russia are reported. In 10 unrelated families, 9 different mutations were identified: Asp47His, Gly232Arg, c.[781_783delAAG, 781insGTGGAGCAGTATAAGAAA], Arg249Gln (in two families), Arg377His, Arg541His, Ala350Pro, Leu52Pro, and Gly635Asp. Mutations Arg249Gln, Arg377His, and Arg541His were reported previously, others are novel. Four cases present de novo mutations, among them two cases with Arg249Gln are found. Because this mutation occurred de novo also in other reported cases, a mutational 'hot spot' was supposed. Three phenotypes were observed: autosomal dominant (AD) Emery-Dreifuss muscular dystrophy (EDMD), limb-girdle MD type 1B, and AD dilated cardiomyopathy with conduction defect type 1A (DCM1A). Atypical clinical presentations were a very severe EDMD and an infantile DCM1A.

[Prevalences of hereditary diseases in various populations in Russia].

The geographic distribution of hereditary diseases (HDs) in different populations and ethnic groups of Russia has been studied. The main patterns of the formation of the prevalence and spectrum of HDs in five ethnic groups (Russians from six regions, Mari, Chuvashes, Udmurts, and Adygeans) from a total of ten regions of Russia have been analyzed. Analysis of correlations suggests that genetic drift is the main factor of the genetic differentiation of populations with respect to the prevalence of HDs. Accumulation of HDs in individual populations and ethnic groups has been analyzed. Hereditary diseases characterized by locally high prevalence rates in individual populations or ethnic groups have been detected. The main patterns of the accumulation of individual diseases and differences between populations and ethnic groups in this respect have been studied with the use of principal component analysis, which describes these patterns more graphically. It has been demonstrated that the genes of HDs are a promising tool for characterizing ethnogenetic processes in populations.

[Genetic structure of the Udmurt population].

Integrated study of the genetic structure of the Udmurt population with respect to different genetic systems has been performed. Data on the genes of genetic diseases, abiotic parameters analyzed by population statistic methods, and DNA polymorphism are summarized. The populations of six raions (districts) of Udmurt Republic (the Mozhga, Malaya Purga, Sharkan, Debesy, Igra, and Glazov raions) have been studied. The total population studied was 267,655 people (an urban population of 150,119 people and a rural population of 117,536 people), including 155,346 Udmurts. The population structure has been studied in six districts on the basis of the vital statistics, Crow's indices, Malecot's isolation by distance parameters, ethnically assortative marriage parameters, endogamy indices, inbreeding-endogamy (ie) indices, and frequencies of the genotype and allele frequencies of four DNA markers (17 alleles). The prevalences of hereditary diseases have been calculated for different population groups: urban and rural populations, Udmurts and other ethnic groups. These groups, especially the urban and rural populations, substantially differed from one another in the prevalences of autosomal dominant (AR) and autosomal recessive (AR) diseases. The correlation between the prevalence of AD and AR diseases and the ie index is positive and significant. The spectrum of hereditary diseases detected in six districts of Udmurtia comprises 149 diseases (80, 57, and 12 AD, AR, and X-linked diseases, respectively). Accumulation of individual diseases in districts of Udmurtia and accumulation of diseases in Udmurtia as compared to regions studied earlier has been found. Cluster analysis of the frequencies of genes of AD and AR diseases and DNA markers has determined the gene geographic position of Udmurts.

[Population study of the Udmurt population: analysis of ten polymorphic DNA loci of the nuclear genome].

Genetic structure of Southern and Northern ethnographic groups of the Udmurt population from six regions of the Republic of Udmurtia has been studied. All the samples were examined using ten polymorphic DNA loci: VNTR/PAH, VNTR/ApoB, VNTR/DAT1, VNTR/eNOS, ACE, CCR5delta32, KM19, IVS6a, THOI, and FABP2. Allelic and genotype frequencies were estimated for each of the six populations. The average heterozygosity for these ten polymorphic loci varied from 0.47 in Udmurts from Glazovskii region to 0.53 in Udmurts from Malopuginskii region. The level of genetic variation (F(ST)) between populations of Udmurts was 0.0048. Ethnographic subdivision of the population into Northern and Southern Udmurts is in good agreement with the values of genetic distances and phylogenetic analysis.

High incidence of mutations in BRCA1 and BRCA2 genes in ovarian cancer.

The incidence of mutations in the BRCA1 and BRCA2 genes in the studied sampling of 74 patients with ovarian cancer was 19%. The incidence of mutations in the Russian sampling of patients, formed without consideration for the family history, is one of the highest in European countries. Retrospective analysis showed that 9% patients carrying mutation had no family history of ovarian or breast cancer. The majority of mutations (86%) were detected in BRCA1 gene, where 5382insC mutation predominated (58%). These data suggest the possibility and advisability of screening for mutations in the BRCA1/2 genes in patients with ovarian cancer, particularly because this population includes patients without family history of ovarian and/or breast cancer.

[Analysis of polymorphism at nine nuclear genome DNA loci in maris].

Population genetic survey of the indigenous populations of the Marii El Republic, represented by the two major ethnographic groups of Maris, Meadow (five samples from Morkinsk, Orshansk, Semursk, Sovetsk, and Zvenigovsk districts) and Mountain (one sample from Gornomariisk district) Maris, was carried out. All Mari groups were examined at nine polymorphic DNA loci of nuclear genome, VNTR(PAH) (N = 422), STR(PAH) (N = 152), VNTR(ApoB) (N= 294), VNTR(DAT1) (N = 363), VNTR(eNOS) (N = 373), ACE (N = 412), IVS6aGATT (N = 513), D7S23(KM.19) (N = 494), and D7S8 (N = 366). Allele and genotype frequency distribution patterns were obtained for individual samples and ethnographic groups, as well as for the ethnic group overall. In each of six Mari samples examined, the deficit of heterozygotes was observed, i.e., the mean observed heterozygosity was lower than the expected one. The indices of mean heterozygosity, Hs = 0.455, and interpopulation differentiation, FST = 0.0024, for the Mari gene pool were obtained using a set of DNA markers analyzed. Analysis of the genetic distances and between population differentiation (FST) showed that the main part of genetic diversity in Maris was determined by the differentiation between the populations of Meadow Maris. The contribution of the differences between the ethnographic groups of Mountain and Meadow Maris to the ethnic gene pool was small. It is suggested that the main role in the formation of the Mari gene pool is played by the geographic factor.

New mutations in the APC gene in familial adenomatous polyposis: detection, characterization, and analysis.

The spectrum of mutations in the APC gene in familial adenomatous polyposis was detected in a sampling from the Russian population. Fifteen new mutations were found. Deletions associated with the loss of only 1 or 2 nucleotides (89% cases) prevailed among new (unique) mutations, while all known deletions were caused by the loss of 4 or 5 nucleotides. The detected differences in the deletion characteristics between unique and repeated mutations in the APC gene were typical of samples of patients from a number of populations. Samplings from different populations were heterogeneous by this sign. The incidence of 1-2-nucleotide deletions among unique and repeated deletions in the APC gene in patient samplings from different countries were in negative correlation.

[Integrated population genetic and medical genetic study of two raions of the Tver oblast]. / Kompleksnoe populiatsionno- i mediko-geneticheskoe issledovanie naseleniia dvukh raionov Tverskoi oblasti.

An integrated medical genetic an population genetic study has been performed in two raions (administrative districts) of the Tver oblast (region) of Russia: the Udomlya raion located in the zone affected by the Kalininskaya Nuclear Power Plant and the Ostashkov raion, which served as a control district. No significant differences has been found with respect to the genetic parameters studied. The values of these parameters in the populations of the town of Udomlya, the town of Ostashkov, the Udomlya raion, and the Ostashkov raion, respectively, are the following: random inbreeding, 0.00006, 0.00011, 0.000167, and 0.000366; endogamy index, 0.05, 0.43, 0.30, and 0.42; local inbreeding, 0.0003, 0.00045, 0.0009, and 0.0011; the degree of isolation by distance, 0.0003, 0.00045, 0.0009, and 0.0005; sigma, 2098, 1338, 1473, and 1189; the load of autosomal dominant (AD) diseases, 0.71, 0.92, 0.92, and 1.37; the load of autosomal recessive (AR) diseases, 0.68, 0.69, 0.67, and 0.82; and the load of X-linked diseases, 0.18, 0.64, 0.83, and 0.27.