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The review is devoted to the genetic nature of congenital glaucoma (CG) and presents clinical and genetic forms of hereditary glaucoma and single nucleotide polymorphisms identified by genome-wide association studies (GWAS). Glaucoma is a genetically heterogeneous disease, and patients with the same clinical diagnosis often have different molecular causes. The role of mutations in the CYP1B1 gene has been proven in the pathogenesis of hydrophthalmos; the MYOC gene — in juvenile open-angle glaucoma; the PAX6 gene — in aniridia; mutations in the PITX2, FOXC1 genes have been identified in Axenfeld-Rieger anomaly/syndrome. It has been established that 4–43% of patients with open-angle glaucoma have a family history of a mutation in the MYOC, OPTN or TBK1 genes. Genetic studies of glaucoma are the first steps to developing a new generation of personalized treatments. The article describes the key features of the pathogenesis of various genetic forms of glaucoma and the possible course of its therapy. However, gene therapy requires further study of both long-term effects and efficacy. Molecular genetic diagnosis of glaucoma allows for personalized genetic counseling of family members with consideration of the genetic risks.

On the basis of the data from the archive of the Laboratory of Genetic Epidemiology of the Research Centre for Medical Genetics, marriage records are selected for three large cities of the North Caucasus with a significant proportion of Russians: Vladikavkaz (25% Russians), Mozdok (59%), and Cherkessk (54%). In the selected marriage records, one or both spouses are Russian. The places of birth of migrants are analyzed at the level of federal districts. It is shown that three quarters of the Russian population of North Caucasian cities are natives of the North Caucasian Federal District. The majority of Russian migrants are natives of Ukraine and Kazakhstan.

X-linked juvenile retinoschisis is a hereditary eye disease that belongs to the group of retinal dystrophy. This study presents the results of the search for mutations in the RS1 gene in 48 unrelated men diagnosed with X-linked juvenile retinoschisis. Molecular genetic diagnosis was found in 77% of the probands. Revealed were 27 different pathogenic variants, including eight novel, previously not described. The spectrum of mutations in the RS1 gene in a Russian cohort of patients is characterized by high diversity and the absence of major mutations.

The purpose: to describe clinical cases of oculodental-digital dysplasia (ODDD, OMIM #164200) with mutation in GJA1 (OMIM 121014) with molecular genetic verification of the diagnosis.Methods. The article describes the clinical case of oculodental-digital dysplasia in a 51 years old patient. Patient underwent full ophthalmic examination including autorefractometry, visual acuity testing with full correction, tonometry, biomicroscopy, fundus examination and photo as well as kinetic perimetry, autofluorescence and optical coherence tomography (OCT) of macula and optic disk were performed. Electrophysiological examination included Visual Evoked Potentials (VEP) to flash and pattern stimulation, ISCEV standard electroretinograms (ERG) and macular ERG. For the verification of the diagnosis and pathologic gene molecular genetic examination was performed with family anamnesis previously attained.Results. The patient was complaining the deterioration of vision, hearing loss and the sense of smell. Visual deterioration was associated with nyctalopia. Natural history revealed glaucoma 2а which was diagnosed when he was 48 years old. Best corrected visual acuity was 1,0. Peripheral visual field defects were revealed bilaterally. High visual acuity correlated with normal foveal structure on OCTs the retinal nerve fiber layer (RNFL) was thinner than normal in temporal half; deep excavation was visualized in both eyes. Normal MERG and bilateral decrease of scotopic, maximal full-field ERG was recorded which correlated with nyctalopia, as well as subnormal photopic responses indicating cone system involvement. The genetics revealed characteristic features of the face: a small nose with hypoplasia of the wings of the nose, unfolded nostrils and a wide bridge of the nose (pseudohypertelorism). On right-wing the ear sink was detected 2 antitraguses. Changes fingers upper extremities — operated syndactyly IV and V on the background of brachydactyly of the fingers. On the legs on both sides — syndactyly III–IV. 10 years the sense of smell has been dereriorated. In the study of DNA in proband in direct Sanger sequencing of all exons 1–2 and regions of exon-intron compounds of gene GJA1, was found the pathogenic variant in second exon c.412G>A (p.Gly138Ser) in heterozygous state. Was established autosomal dominant type of disease.Conclusion. We are the first to describe rod-cone dystrophy in oculodental-digital dysplasia.

The results of the study of genetic load and diversity of monogenic forms of hereditary pathology (MHP) among the child population from 11 districts of Kirov region (KR) obtained during genetic and epidemiological study of the region are presented. The total size of surveyed population is 286 616 individuals (including 37 348 children—13.03%), mainly Russians (88.1%). MHP included 91 diseases (287 patients from 255 families): 50 with autosomal dominant (AD) inheritance (153 patients from 129 families), 33 with autosomal recessive (AR) (107 patients from 104 families), and 8 nosologies with X-linked inheritance (27 patients from 22 families). All diseases were found in previously surveyed populations of the Russian Federation. Nine forms of MHP were detected with a prevalence higher than 1 : 5000: hereditary motor-sensory neuropathy (21.42/100 000), AD ichthyosis vulgaris (83.00/100 000), AD congenital ptosis (24.10/100 000), AD congenital cataract (29.45/100 000), AD syndactyly, type 1 (24.10/100 000), AR undifferentiated mental retardation (26.76/100 000), AR microcephaly with mental retardation (50.87/100 000), AR congenital cataract (26.78/100 000), and AR nonsyndromic sensorineural hearing loss (58.91/100 000). The average prevalence of MHP among the child population of KR was 1 : 130 children, with variation from 1 : 236 children in Vyatskopolyansky district to 1 : 51 children in Sunsky district. On the basis of the correlation analysis between load estimations and Fst values carried out, the reasons for revealed differentiation between districts are assumed.

Background Hereditary ophthalmic pathology is a genetically heterogeneous group of diseases that occur either as an isolated eye disorder or as a symptom of hereditary syndromes (chromosomal or monogenic). Thus, a diagnostic search in some cases of ophthalmic pathology can be time- and cost-consuming. The most challenging situation can arise when prenatal diagnosis is needed during an ongoing pregnancy. Case presentation A family was referred to the Research Centre for Medical Genetics (RCMG) for childbirth risk prognosis at 7–8 week of gestation because a previous child, a six-year-old boy, has congenital aniridia, glaucoma, retinal detachment, severe psychomotor delay, and lack of speech and has had several ophthalmic surgeries. The affected child had been previously tested for PAX6 mutations and 11p13 copy number variations, which revealed no changes. Considering the lack of pathogenic changes and precise diagnosis for the affected boy, NGS sequencing of clinically relevant genes was performed for the ongoing pregnancy; it revealed a novel hemizygous substitution NM_000266.3(NDP):c.385G > T, p.(Glu129*), in the NDP gene, which is associated with Norrie disease (OMIM #310600). Subsequent Sanger validation of the affected boy and his mother confirmed the identified substitution inherited in X-linked recessive mode. Amniotic fluid testing revealed the fetus was hemizygous for the variant and lead to the decision of the family to interrupt the pregnancy. Complications which developed during the termination of pregnancy required hysterectomy due to medical necessity. Conclusions Clinical polymorphism of hereditary ophthalmic pathology can severely complicate establishment of an exact diagnosis and make it time- and cost-consuming. NGS appears to be the method-of-choice in complicated cases, and this could substantially hasten the establishment of a diagnosis and genetic risk estimation.

A cartographic analysis of the values of random inbreeding obtained by the isonymy method, as well as the Barrai parameters considered as an extension of the isonymy method, was carried out. In North Ossetia, two opposite extremes with different degrees of expressiveness—in the Mozdoksky and Irafsky districts—were revealed.

Based on 28 359 marriage records for 1990–2000 throughout the Republic of North Ossetia-Alania, endogamy indices were calculated for different categories of the population of the republic: for the entire population in each district, for the urban and rural population, for the main ethnic groups. The cartographic analysis showed a reduction of endogamy in the direction of west to east. The obtained values of endogamy positively correlate with the values of random inbreeding. It is shown that the Republic of North Ossetia–Alania is not a population of the highest hierarchical level; the Ossetian people live on the territory of two republics, North and South Ossetia, without losing family ties, despite the presence of borders.

BackgroundAniridia is a severe autosomal dominant panocular disorder associated with pathogenic sequence variants of the PAX6 gene or 11p13 chromosomal aberrations encompassing the coding and/or regulatory regions of the PAX6 gene in a heterozygous state. Patients with aniridia display several ocular anomalies including foveal hypoplasia, cataract, keratopathy, and glaucoma, which can vary in severity and combination.MethodsA cohort of 155 patients from 125 unrelated families with identified point PAX6 pathogenic variants (118 patients) or large chromosomal 11p13 deletions (37 patients) was analyzed. Genetic causes were divided into 6 types. The occurrence of 6 aniridic eye anomalies was analyzed. Fisher’s exact test was applied for 2×2 contingency tables assigning numbers of patients with/without each sign and each type of the PAX6 variants or 11p13 deletions with Benjamini–Hochberg correction. The age of patients with different types of mutation did not differ.ResultsPatients with 3′-cis-regulatory region deletions had a milder aniridia phenotype without keratopathy, nystagmus, or foveal hypoplasia. The phenotypes of the patients with other rearrangements involving 11p13 do not significantly differ from those associated with point pathogenic variants in the PAX6 gene. Missense mutations and genetic variants disrupting splicing are associated with a severe aniridia phenotype and resemble loss-of-function mutations. It is particularly important that in all examined patients, PAX6 mutations were found to be associated with multiple eye malformations. The age of patients with keratopathy, cataract, and glaucoma was significantly higher than the age of patients without these signs.ConclusionWe got clear statistically significant genotype-phenotype correlations in congenital aniridia and evident that aniridia severity indeed had worsened with age.

Malecot’s model of isolation by distance was used to describe the population structure of the population of North Ossetia-Alania based on 12 308 marriage records for a population of the rank of “republic.” A number of positive correlations were obtained with the results of previous studies. The difference between the Mozdoksky district and other districts of the republic is confirmed.

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.

This paper carries out a comparative analysis of standard population-genetic parameters based on the distribution of surnames and marriage migrations in the Digorsky and Ardonsky districts. The positive and significant correlation of all the considered parameters allowed concluding that it is possible to use Ossetian surnames (of both Irons and Digors) as a biological marker in population-genetic studies.

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, Malecot’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.

The article describes a clinical case of a 14-year old patient with RDH5 mutations (OMIM *601617) in patient with fundus albipunctatus (OMIM #136880) and characteristic biomarkers of this disease with previously described pathogenic variant of nucleotic sequence in exon 3 of the RDH5 gene (NM_002905.3:c.500GA), causing a missense change (p.Arg167His) in heterozygous state and previously not described pathogenic variant of nucleotic sequence in exon 5 of the RDH5 gene (NM_002905.3:c.838CT), leading to a missense change (p.Arg280Cys) in heterozygous state with characteristic biomarkers of the disease. Best-corrected visual acuity (BCVA) was 20/20. Nyctalopia was accompanied by reduced b-wave of scotopic (dark-adapted 0.01) ERG and decreased amplitude of a- and b-waves of maximum (dark-adapted 3) ERG. Decreased amplitude of the a- and b-waves of photopic (light-adapted 3) ERG and the amplitude of high-frequency (light-adapted 30 Hz) Flicker ERG shows the involvement of retinal cone system in the process. Fundus autofluorescence imaging of both eyes produced fuzzy and grainy images with slight hyperfluorescence of retinal flecks. Optical coherence tomography showed focal thickening centered in the photoreceptor outer segment corresponding to the multiple discrete albipunctate dots.В статье описывается клинический случай белоточечного глазного дна (fundus albipunctatus, OMIM #136880) с мутациями в гене RDH5 (OMIM *601617) в 3-м экзоне гена RDH5 (NM_002905.3:c.500GA), приводящий к образованию миссенс-замены (p.Arg167His) в гетерозиготном состоянии и не описанный ранее как патогенный вариант нуклеотидной последовательности в 5-м экзоне гена RDH5 (NM_002905.3:c.838CT), приводящий к образованию миссенс-замены (p.Arg280Cys) в гетерозиготном состоянии с характерными биомаркерами этого заболевания у пациента 14 лет. Острота зрения с коррекцией составила OU 1,0. Жалобы на ухудшение зрения в темноте сопровождались снижением амплитуды b-волны скотопической электроретинографии (ЭРГ) и a- и b-волн максимальной ЭРГ. Снижение амплитуды a- и b-волн фотопической ЭРГ и амплитуды высокочастотной ритмической ЭРГ на 30 Гц свидетельствовало о вовлечении в процесс колбочковой системы сетчатки. На аутофлюоресцентных изображениях глазного дна визуализировались нечеткие, зернистые, слегка гиперфлюоресцирующие очажки. На изображениях, полученных при оптической когерентной томографии, визуализировались фокальные утолщения с центром в наружных сегментах фоторецепторов, соответствующие множественным дискретным белоточечным пятнам.

Introduction Mitochondrial membrane protein-associated neurodegeneration (MPAN) is a rare neurological syndrome caused by pathogenic variants in the C19orf12 and is characterized by iron deposition in the basal ganglia and substantia nigra. Only a limited number of cohort studies were published to date and the prevalence of MPAN remains uncertain. Methods Recruited subjects with MPAN in Russia were diagnosed by whole-exome sequencing or Sanger sequencing of the C19orf12 gene. Data of over 14000 whole exome sequencing analyses was used to calculate the estimated disease frequency. RNA analysis was performed by RT-PCR. QSVanalyzer software was used to quantify the allelic disbalance. Results We describe the clinical and molecular characterizations of 17 patients with MPAN. DNA analysis detected three previously undescribed pathogenic/likely pathogenic variants in the C19orf12 gene. The estimated disease frequency was calculated to be 1:619150. We describe unusual clinical observations in several cases. One patient showed severe neurogenic muscle weakness along with a lack of marked spasticity or optic nerve atrophy. In another mild clinical case with the NM_001031726.3:c.204_214del (p.(Gly69Argfs*10)) variant in a heterozygous state, a marked allelic disbalance was observed on the RNA level with reduced expression level of the wild-type allele. Thus, this case became the first one of a possible regulatory variant causing MPAN. Conclusion We reported a detailed clinical and molecular characterization of the third-largest MPAN cohort. We expanded the mutational and clinical spectrum of MPAN. Moreover, we calculated the estimated MPAN frequency in the Russian population for the first time.

Background Because of the significant occurrence of “WAGR-region” deletions among de novo mutations detected in congenital aniridia, DNA diagnosis is critical for all sporadic cases of aniridia due to its help in making an early diagnosis of WAGR syndrome. Standard cytogenetic karyotype study is a necessary step of molecular diagnostics in patients with deletions and in the patients’ parents as it reveals complex chromosomal rearrangements and the risk of having another affected child, as well as to provide prenatal and/or preimplantation diagnostics. Case presentation DNA samples were obtained from the proband (a 2-year-old boy) and his two healthy parents. Molecular analysis revealed a 977.065 kb deletion that removed loci of the ELP4, PAX6, and RCN1 genes but did not affect the coding sequence of the WT1 gene. The deletion occurred de novo on the paternal allele. The patient had normal karyotype 46,XY and a de novo pericentric inversion of chromosome 11, inv(11)(p13q14). Conclusions We confirmed the diagnosis of congenital aniridia at the molecular level. For the patient, the risk of developing Wilms’ tumor is similar to that in the general population. The recurrence risk for sibs in the family is low, but considering the possibility of gonadal mosaicism, it is higher than in the general population.

Background Mutations in CRYAA, which encodes the α-crystallin protein, are associated with a spectrum of congenital cataract–microcornea syndromes. Results In this study, we performed clinical examination and subsequent genetic analysis in two unrelated sporadic cases of different geographical origins presenting with a complex phenotype of ocular malformation. Both cases manifested bilateral microphthalmia and severe anterior segment dysgenesis, primarily characterized by congenital aphakia, microcornea, and iris hypoplasia/aniridia. NGS-based analysis revealed two novel single nucleotide variants occurring de novo and affecting the translation termination codon of the CRYAA gene, c.520T > C and c.521A > C. Both variants are predicted to elongate the C-terminal protein domain by one-third of the original length. Conclusions Our report not only expands the mutational spectrum of CRYAA but also identifies the genetic cause of the unusual ocular phenotype described in this report.

Retinal dystrophy is highly heterogeneous, "frequent among rare" inherited eye pathology which results in blindness. Though some common forms of retinal dystrophy are associated with well-known and years ago established genes, hundreds of others are found and kept being revealed to be involved in its pathogenesis. In this study for genetic testing, a whole-exome sequencing by next-generation sequencing (NGS) was implied, which included bioinformatic analysis using open algorithms and recommendations on filtering. We reported 6 solved using NGS cases of hereditary retinitis pigmentosa associated with pathogenic variants in the genes PRPF31, IFT140, RGS9, RPGR, RP1.

The diversity and prevalence of hereditary diseases (HDs) among Nogais of the Karachay-Cherkess Republic (KChR) are described. The size of the surveyed KChR population was 387231 individuals, including 3.81% Nogais (14741 individuals). We revealed 36 nosological forms of HDs (110 patients from 81 families): 22 with autosomal dominant (AD) inheritance, 10 with autosomal recessive (AR) inheritance, and 4 with X-linked inheritance. The prevalence of HDs in Nogais was 1: 134. The features of HD diversity in Nogais were determined in comparison with the previously surveyed populations of Russia. The accumulation of Ehlers–Danlos syndrome (1: 388), AD amelogenesis imperfecta (1: 3685), AD ichthyosis (1: 4914), AR nonsyndromic mental retardation (1: 1340), AR Gilbert syndrome (1: 4914), and X-linked inherited deficit of glucose-6-dehydrogenase (1: 1774 males) was established. The analysis of heterozygous carriage of mutations “major” for Russia in the genes of the four following AR diseases in 118 unrelated clinically healthy Nogais (236 analyzed chromosomes) was performed: cystic fibrosis (13 mutations in the CFTR gene: CFTRdele2,3 (21 kb), F508del, I507del, 1677delTA, 2184insA, 2143delT, 2183AA>G, 2184delA, 394delTT, 3821delT, L138ins, E92K, W1282X); phenylketonuria (six frequent mutations in the PAH gene: R261X, R408W, R413P, F331S, P211T, P211L); nonsyndromic sensorineural hearing loss (35delG mutation in the GJB2 gene); and Gilbert syndrome (an increase in the number of TA repeats in the UGT1A1 gene). Allelic specificity for all studied genes in the Nogai people was revealed.

This paper estimates the load and nosological spectrum of monogenic hereditary diseases (HDs) in Abazins of the Karachay-Cherkess Republic (KChR), identified in Cherkessk and ten districts, Abazinsky, Ust-Dzhegutinsky, Malokarachaevsky, Karachaevsky, Prikubansky, Khabezsky, Nogaysky, Adyge-Khablsky, Urupsky, and Zelenchuksky. The number of the investigated population was 387231 individuals (including 33264 Abazins). We detected 153 patients from 105 families with 45 nosological forms of HDs: 83 patients from 50 families with 23 AD diseases, 47 patients from 42 families with 15 AR diseases, and 23 patients from 13 families with 7 X-linked diseases. The total load of HDs in Abazins was 1: 218 individuals (in the rural population 1: 162, in the urban population 1: 305). Frequent and rare nosological forms of HDs and the accumulation of certain diseases in Abazins in comparison with the previously surveyed populations of Russia were determined. On the basis of the prevalence of AD and AR hereditary diseases, a principal component analysis was carried out, which determined the genogeographical position of Abazins among nine ethnic groups (13 populations) of Russian Federation: six Russian regions, Bashkirs of the Bashkortostan, Tatars of the Tatarstan, Chuvashes of the Chuvashia, Maris of the Mari El, Udmurts of the Udmurtia, Adygeans of the Adygea, and Circassians and Abazins of the KChR.

V.V. Kadyshev1, A.V. Marakhonov1, S.I. Kutsev1,2, R.A. Zinchenko1,3 1 Research Centre of Medical Genetics of the Russian Academy of Medical Sciences, Moscow,Russian Federation 2 Pirogov Russian National Research Medical University, Moscow, Russian Federation 3 M. F. Vladimirsky Moscow Regional Research and Clinical Institute (MONIKI), Moscow,Russian Federation Abstract The publication continues the previously presented data on the study of the epidemiology of ophthalmic diseases in the children of the Karachay-Cherkess Republic. Genetic epidemiological study of the population includes the study of a wide range of aspects. The structure of the nosological spectrum was published previously. The study of the genetic load is an integral part of this work. Aim: the purpose of this study was to investigate the specific features of the genetic load of hereditary non-syndromic ophthalmologic pathology in the population of the Karachay-Cherkess Republic. Patients and Methods: 90 793 children from 10 districts of the Karachay-Cherkess Republic aged 0–18 were examined, of which 121 were included in the sample. The biomaterial (peripheral venous blood) is taken from a part of patients taking into account the legislative and legal standards of the Russian Federation. In the study, genetic-epidemiological, statistical, molecular-genetic methods of examination were used. Results: the values of genetic load of non-syndromic hereditary eye pathology in the child population of 10 districts of the Karachay-Cherkess Republic and the city of Cherkessk is established. The total load of the non-syndromic hereditary pathology of the eye was 1.33±0.12. Statistical analysis of the obtained genetic load data demonstrated significant differences between autosomal dominant pathology in rural and urban populations (for rural population — t=2.3, for urban — t=2.8). The group of patients underwent confirmatory molecular genetic diagnosis. Conclusions: 1. The genetic load of the hereditary pathology of the organ of vision in the Karachay-Cherkess Republic among children was 1.33±0.12. 2. The prevalence of AD pathology over diseases with AR inheritance in both rural and urban subpopulations was revealed. 3. Region-specific molecular genetic markers for the hereditary pathology of the organ of vision are not established at this stage. Key words: epidemiology, genetics, genetic load, DNA diagnosis, children, Karachay-Cherkess Republic. For citation: Kadyshev V.V., Marakhonov A.V., Kutsev S.I., Zinchenko R.A. Study of the hereditary non-syndromic ophthalmological pathology of child population of the Karachay-Cherkess Republic: estimations of genetic load and molecular genetic analysis.RMJ “Clinical ophthalmology”. 2018;3:134–139.

Vasilyeva T. A.1, Voskresenskaya A. A.2, Kadyshev V. V.1, Pozdeyeva N. A.2, Marakhonov A. V.1,3, Zinchenko R. A.1,4 1 Research Center for Medical Genetics, Moscow 2 Cheboksary branch of S. Fyodorov Eye Microsurgery Federal State Institution 3 Moscow Institute of Physics and Technology (State University), Dolgoprudny 4 Pirogov Russian National Research Medical University, Moscow Introduction: congenital aniridia (AN) is a Mendelian autosomal dominant disorder (population prevalence 1:57143). AN might occur as a part of WAGR syndrome (~13%). The main diagnostic signs of AN are absence of iris and fovea hypoplasia accompanied by nystagmus. Patients also show other eye structures as well as central nervous system anomalies. AN is caused by heterozygous mutations of the PAX6 gene or chromosome rearrangements of 11p13 region. There are no established correlation between the type of PAX6 mutation and the features of aniridia clinical picture. Aim: the paper is to analyze probable relations between AN clinical features and the type of PAX6 mutation. Patients and Methods: 98 patients with AN from 73 unrelated families with identified small PAX6 mutations (74 patients) and large chromosomal 11p13 deletions (24 patients) were analyzed. Patients were divided into the groups according to the type/location of mutation. Phenotypic traits were referred to the type/location of mutation. Contingency tables 2X2 were analyzed by the exact Fisher test. Results: AN clinical picture associated with loss of function mutations (nonsense, frame shift and splicing) has more severe clinical course. Missense mutations are associated with character phenotype of general sample, however, partial aniridia occurs significantly more often. Phenotypes of patients with chromosomal deletions (without deletions of the 3′ cis-regulatory region), do not differ from that of patients with intragenic mutations. A milder phenotype is observed in patients with deletions of the 3′ cis-regulatory region. Key words: congenital aniridia, PAX6 mutations, chromosome region 11p13 deletions, relationships between mutation type and clinical trait. For citation: Vasilyeva T.A., Voskresenskaya A.A., Kadyshev V.V. at all. Clinical and molecular-genetic features of congenital aniridia // RMJ “Clinical ophthalmology”. 2018;1:7–12.

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.

To describe the population-genetic structure of the Russian population of Karachay-Cherkessia, the database of Compulsory Medical Insurance and marriage records for 1990–2000 were used. The Russian population is characterized by a low birth rate, low endogamy, low inbreeding, and a high level of miscegenation.

WAGR syndrome (OMIM #194072) is a rare genetic disorder that consists of development of Wilms’ tumor (nephroblastoma), aniridia, genitourinary anomalies and intellectual disability (mental retardation). It is associated with WAGR-region deletions in the 11p13 chromosome region. Our previous study of congenital aniridia patients revealed a noticeable number of aniridia patients with WAGR-region deletions but without Wilms’ tumor in their medical history. We assessed the involvement of other neighboring genes from affected chromosome regions in the patients with and without Wilms’ tumor. Reliable confidence was obtained for the LMO2 gene, which is significantly more often deleted in patients with nephroblastoma. Thus, our study presents genetic evidence that the development of Wilms tumors in WAGR syndrome patients should be attributed to the deletion of WT1 and LMO2 rather than WT1 only.

Background Primary microcephaly represents an example of clinically and genetically heterogeneous condition. Here we describe a case of primary microcephaly from the Karachay-Cherkess Republic, which was initially diagnosed with Seckel syndrome. Case presentation Clinical exome sequencing of the proband revealed a novel homozygous single nucleotide deletion in ASPM gene, c.1386delC, resulting in preterm termination codon. Population screening reveals allele frequency to be less than 0.005. Mutations in this gene were not previously associated with Seckel syndrome. Conclusions Our case represents an additional support for the clinical continuum between Seckel Syndrome and primary microcephaly.

To evaluate phenotype-genotype correlations in patients with inherited retinal diseases (IRD) with mutation p.G1961E in the ABCA4 gene.The study included 20 patients with p.G1961E mutation in the heterozygous state in the ABCA4 gene who underwent complete ophthalmic examination, as well as high-performance parallel sequencing of the coding sequences and adjacent areas of the introns of the ABCA4, ELOVL4, PROM1, CNGB3 genes.The p.G1961E mutation was detected in heterozygous state with missense mutations, splice site mutations, a frameshift duplication, and a nonsense mutation in 18 patients, a second mutation was not detected in 2 patients. The duration of the disease in 4 patients was 2-5 years, which made it impossible to assess the morphofunctional changes in dynamics. In 13 of the 16 patients with IRD duration of 29±14 years and p.G1961E mutation in the ABCA4 gene the course of the disease was relatively mild: visual acuity of 0.15±0.07, loss of visual acuity averaging 0.037±0.019 per year, absolute/relative scotoma within 5-20°, and 3.52±1.21 mm loss of ellipsoid photoreceptor zone in the macular area according to OCT. In 3 patients, including one without a second mutation in the ABCA4 gene, better pronounced changes were revealed. Multifocal electroretinogram was altered in all 20 cases. In 7 of the 8 patients with p.G1961E in the heterozygous state in combination with complex mutation p.[L541P;A1038V], as well as in 2 patients without a second mutation, full-field electroretinography (Ganzfeld; ffERG) had changes (abnormalities) of varying intensity.A frequent mutation in the ABCA4 gene - p.G1961E - is associated with a relatively mild course of IRD in 81% of cases, even in the presence of a second, severe mutation. However, in rare cases a more severe phenotype of the IRD in patients with p.G1961E mutation can be observed, which may be associated with other genetic factors. In patients with the p.G1961E mutation in heterozygous state with p.[L541P;A1038V], ffERG changes (abnormalities) were revealed.Цель исследования - оценить клинико-генетические корреляции у пациентов с наследственными заболеваниями сетчатки (НЗС) с мутацией p.G1961E в гене АВСА4. Материал и методы. Пациентам (n=20) с НЗС с мутацией p.G1961E в компаунд-гетерозиготном состоянии в гене АВСА4 проводили обследование с применением стандартных и дополнительных офтальмологических методов исследования, а также высокопроизводительное параллельное секвенирование кодирующих последовательностей и прилежащих участков интронов генов ABCA4, ELOVL4, PROM1, CNGB3. Результаты. Мутация p.G1961E выявлена в гетерозиготном состоянии с миссенс-мутациями, мутациями сайта сплайсинга, дупликацией со сдвигом рамки считывания и с нонсенс-мутацией у 18 человек, у 2 пациентов вторая мутация не обнаружена. Длительность заболевания 4 пациентов составила 2-5 лет, что не дало возможности оценить морфофункциональные изменения в динамике. Из 16 пациентов с длительностью НЗС 29±14 лет и мутацией p.G1961E в гене АВСА4 относительно легкое течение заболевания отмечено у 13 человек: острота зрения 0,15±0,07, потеря остроты зрения в среднем 0,037±0,019 в год, центральная абсолютная/относительная скотома в пределах 5-20°, потеря эллипсоидной зоны фоторецепторов в макулярной зоне по данным оптической когерентной томографии (ОКТ) 3,52±1,21 мм. У 3 пациентов выявлены более выраженные морфофункциональные изменения, в том числе у 1 пациента без верифицированной второй мутации гена АВСА4. Мультифокальная электроретинограмма изменена у всех пациентов. У 7 из 8 пациентов с мутацией p.G1961E в сочетании с комплексной мутацией p.[L541P;A1038V], а также у 2 пациентов без выявленной второй мутации обнаружены в разной степени выраженные изменения ганцфельд-электроретинограммы. Заключение. Частая мутация гена ABCA4 p.G1961E в 81% случаев ассоциирована с легким течением НЗС, даже при наличии второй тяжелой мутации. Однако в редких случаях встречается более тяжелый фенотип НЗС с мутацией p.G1961E, что, вероятно, обусловлено другими генетическими факторами. У пациентов с мутацией p.G1961E в гетерозиготном состоянии с гаплотипом p.[L541P;A1038V] выявлены изменения показателей ганцфельд-электроретинограммы.

In most cases, age-related macular degeneration (AMD) and glaucoma are considered multi-factor diseases that lead to irreversible blindness in senior population of developed countries. Among different types of these diseases, around 5% are monogenic. Studying their molecular and genetic aspects can lay the basis for improvement of diagnostic methods, prognosis of the risks of development, manner of progression and treatment outcomes, as well as creation of new therapy methods. The article reviews modern understanding of the etiopathogenesis of AMD and glaucoma and describes their interrelations.Возрастная макулярная дегенерация (ВМД) и глаукома в настоящее время в большинстве случаев считаются мультифакториальными заболеваниями, приводящими к развитию необратимой слепоты у пожилых людей в развитых странах. К моногенным формам заболеваний данной группы в настоящее время относится примерно 5%. Изучение молекулярно-генетических аспектов данных видов патологии служит основой для совершенствования диагностических методов, прогнозирования риска развития, течения заболевания и результатов лечения, а также для разработки новых методов терапии. В обзоре объединены современные концепции этиопатогенеза ВМД и глаукомы, описана их взаимосвязь.

The distribution of surnames in for populations of the district rank in Kirov oblast has been used to calculate Barrai’s parameters, which are the following: Ir, 0.0008–0.0208; H, 6.80-211.57; ν, 0.003–0.058; α, 47.35–1191.39; R, 23.03–50.07. The results have been compared with data on the 1980s; no substantial changes in the studied parameters during a generation have been found.

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.

The distribution of surnames in for populations of the district rank in Kirov oblast has been used to calculate Barrai's parameters, which are the following: Ir, 0.0008-0.0208; H, 6.80-11.57; v, 0.003-0.058; alpha, 47.35-1191.39; R, 23.03-50.07. The results have been compared with data on the 1980s; no substantial changes in the studied parameters during a generation have been found.