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Introduction. Financing of drug maintenance for patients with rare diseases has been remained one of the main topics in Russian Federation (RF) healthcare. The aim of this article is to present data regarding financing of drug maintenance for patients with life-threatening and chronic progressive rare diseases leading to a reduced life expectancy and disability. Materials and methods. There are considered changes in regional financing structure before (2018) and after (2020) the decision on the redistribution of drug maintenance financing from regional to the federal level for patients with hemolytic uremic syndrome, mucopolysaccharidosis type I, II, VI, juvenile arthritis with systemic onset, unspecified aplastic anemia, hereditary deficiency of factors II (fibrinogen), VII (labile), X (Stuart–Prower). Results. Over 2020, only in 2 regions of the Russian Federation, the cost of drug provision for patients with rare diseases from the “List of life-threatening and chronic progressive rare (orphan) diseases leading to a reduction in life expectancy of citizens or their disability” at the regional level exceeded 500 million rubles in comparison with 6 regions in 2018. In addition, the threshold of 200 million rubles was exceeded in all regions included in the list of 20 regions of the Russian Federation with the highest expenses for drug provision of patients with mentioned rare diseases at the regional level in 2018, while in 2020, only 15 regions spent more than the indicated threshold. Limitations. The number of Russian regions with large expenditures from regional funds on drug provision for patients with rare diseases were 20 regions in 2018 and 2020. Conclusion. Consistent federalization of drug provision for patients with certain rare diseases in 2019–2020 led to a decrease in funding for the provision of drugs for rare diseases from regional budgets.

Hemophilia B is a monogenic X-linked recessive disorder associated with blood clotting reduction caused by mutations in the clotting factor IX gene (F9). An unusual form of this disorder, hemophilia B Leyden, caused by mutations in the promoter region of the F9 gene, is described. This form of hemophilia B is characterized by a significant, within norm, increase in factor IX in the patient’s plasma after puberty. Mutations in the promoter are grouped in discrete regions of transcription factor binding sites and alter the F9 gene expression during the ontogeny in different ways. This disorder demonstrates how single-nucleotide pathogenic variants in cis-regulatory regions can have a dramatic impact on gene expression. In this article, we present the current data on the F9 gene promoter structure and the results of examining three patients with hemophilia B Leyden who underwent genetic testing in the DNA-diagnostics laboratory of the Bochkov Research Centre for Medical Genetics.

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.

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.

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

A young boy with multifocal epilepsy with infantile spasms and hypsarrhythmia with minimal organic lesions of brain structures underwent DNA diagnosis using whole‐exome sequencing. A heterozygous amino‐acid substitution p.L519R in a PHACTR1 gene was identified. PHACTR1 belongs to a protein family of G‐actin binding protein phosphatase 1 (PP1) cofactors and was not previously associated with a human disease. The missense single nucleotide variant in the proband was shown to occur de novo in the paternal allele. The mutation was shown in vitro to reduce the affinity of PHACTR1 for G‐actin, and to increase its propensity to form complexes with the catalytic subunit of PP1. These properties are associated with altered subcellular localization of PHACTR1 and increased ability to induce cytoskeletal rearrangements. Although the molecular role of the PHACTR1 in neuronal excitability and differentiation remains to be defined, PHACTR1 has been previously shown to be involved in Slack channelopathy pathogenesis, consistent with our findings. We conclude that this activating mutation in PHACTR1 causes a severe type of sporadic multifocal epilepsy in the patient., Activating nature of the PHACTR1 L519R mutation. Left, PHACTR1 binds multiple G‐actin molecules (shown symbolically by a single red circle) which antagonise formation of the PHACTR1/PP1 complex, which will therefore form only when local G‐actin concentration falls below a threshold. Right, PHACTR1 L519R (star) exhibits reduced G‐actin binding affinity, allowing the PHACTR1/PP1 complex to form at higher G‐actin concentation. The L519R mutation affects PHACTR1 subcellular localisation as well, and it is therefore possible that its phenotype additionally reflects redistribution of PP1.

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.

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.

WAGRO syndrome is a rare genetic syndrome that includes Wilms tumor, aniridia, genitourinary system abnormalities, mental retardation, and obesity. The syndrome is associated with deletions of the short arm of chromosome 11 (11p), where the PAX6 and WT1 genes are located. We present the clinical case of a 7-year-old boy with aniridia, polar cataract, and concomitant neuromotor, psychomotor, and speech delays. Evaluation of the childs karyotype followed by confirmation using multiplex ligation-dependent probe amplification showed the presence of a deletion including in the 11p13-p14 region.

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.

Genome-wide sequencing metadata allows researchers to infer bias in the relative frequencies of mutational events and to predict putative mutagenic models. In addition, much less data could be useful in the evaluation of the mutational frequency spectrum and the prevalent local mutagenic process. Here we analyzed the

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.

North Caucasus has always been a residence of a lot of different authentic ethnic groups speaking different languages and still living their traditional lifestyle. The diversity appeared to be reflected in the accumulation of different mutations causing common inherited disorders. X-linked ichthyosis represents the second most common form of genodermatoses after ichthyosis vulgaris. Eight patients from three unrelated families of different ethnic origin, Kumyk, Turkish Meskhetians, and Ossetian, with X-linked ichthyosis from the North Caucasian Republic of North Ossetia–Alania were examined. NGS technology was implied for searching for disease-causing variants in one of the index patients. Known pathogenic hemizygous deletion in the short arm of chromosome X encompassing the STS gene was defined in the Kumyk family. A further analysis allowed us to establish that likely the same deletion was a cause of ichthyosis in a family belonging to the Turkish Meskhetians ethnic group. In the Ossetian family, a likely pathogenic nucleotide substitution in the STS gene was defined; it segregated with the disease in the family. We molecularly confirmed XLI in eight patients from three examined families. Though in two families, Kumyk and Turkish Meskhetian, we revealed similar hemizygous deletions in the short arm of chromosome X, but their common origin was not likely. Forensic STR markers of the alleles carrying the deletion were defined to be different. However, here, common alleles haplotype is hard to track for a high local recombination rate. We supposed the deletion could arise as a de novo event in a recombination hot spot in the described and in other populations with a recurrent character. Defined here are the different molecular genetic causes of X-linked ichthyosis in families of different ethnic origins sharing the same residence place in the Republic of North Ossetia–Alania which could point to the existing reproductive barriers even inside close neighborhoods.

Intestinal organoids derived from rectal biopsies of cystic fibrosis patients are a highly sensitive personalized method for evaluating the functional activity of the CFTR channel and the efficacy of target drugs. We examined four patients whose genotype contains the pathogenic F508del variant (three patients and one healthy heterozygous person). It was shown that F508del/F508del genotype (two patients) could be effectively corrected by CFTR modulators (VX-770 and VX-809). The modulators had no significant effect on the restoration of the chlorine CFTR channel function in a patient with the W361X/F508del genotype. The CFTR functional activity in the heterozygous F508del carrier was as high as in the healthy control. cystic fibrosis, intestinal organoids, genetic F508del variant, genotype, forskolin-induced swelling (FIS) assay, CFTR modulators This study was supported by the Ministry of Science and Higher Education as part of a State Assignment for RCMG.

Objective. To analyze the association between NOS1, NOS2, NOS3, ARG1, and ARG2 gene polymorphisms and clinical, laboratory, and functional characteristics of bronchial asthma (BA) in children by evaluating gene-gene interactions. Patients and methods. We have evaluated the associations between the NOSs and ARG genes and gene-gene interactions in 107 children with BA. We performed comparative genetic analysis of associations between polymorphic variants of candidate genes in 107 BA patients and clinical manifestations of the disease, laboratory, and functional parameters. Results. We have found an association between the short (S) allele and SS genotype of the NOS1 (AAT)n gene and early disease onset (

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.

Kalmyks, the only Mongolic-speaking population in Europe, live in the southeast of the European Plain, in Russia. They adhere to Buddhism and speak a dialect of the Mongolian language. Historical and linguistic evidence, as well a shared clan names, suggests a common origin with Oirats of western Mongolia; yet, only a limited number of genetic studies have focused on this topic. Here we compare the paternal genetic relationship of Kalmyk clans with ethnographically related groups from Mongolia, Kyrgyzstan and China, within the context of their neighbouring populations. A phylogeny of 37 high-coverage Y-chromosome sequences, together with further genotyping of larger sample sets, reveals that all the Oirat-speaking populations studied here, including Kalmyks, share, as a dominant paternal lineage, Y-chromosomal haplogroup C3c1-M77, which is also present in several geographically distant native Siberian populations. We identify a subset of this clade, C3c1b-F6379, specifically enriched in Kalmyks as well as in Oirat-speaking clans in Inner Asia. This sub-clade coalesces at around 1500 years before present, before the Genghis Khan era, and significantly earlier than the split between Kalmyks and other Oirat speakers about 400 years ago. We also show that split between the dominant hg C variant among Buryats—C3-M407—and that of C3-F6379, took place in the Early Upper Palaeolithic, suggesting an extremely long duration for the dissipation of hg C3-M217 carriers across northern Eurasia, which cuts through today’s major linguistic phyla.

Cystic fibrosis (CF, MIM# 219,700) is an autosomal recessive disease caused by pathogenic variants within the CFTR gene. It was shown that genetic variants located in cis can affect disease severity or treatment response because of additive or epistatic effects. Studies on the prevalence of complex alleles in Russian CF patients have just begun.AimTo evaluate frequencies and genetic background of complex alleles carrying c.1521_1523delCTT (F508del) and c.1399C>T (L467F), c.2562T>G (T854=) or c.4389G>A (Q1463=) in cis; to determine clinical consequences of complex allele c.[1399C>T;1521_1523delCTT] ([L467;F508del]) in Russian CF patients.MethodsSequencing of coding regions of CFTR gene and analysis of polymorphic markers in CF patients carrying F508del variant. Comparing of clinical features in two groups patients having genotypes [L467F;F508del];[F508del] (group 1) and [F508del];[F508del] (group 2).ResultsFrequency of [L467F;F508del] allele linked to 2–2–21–6–17–13 haplotype was 4.42%, of [F508del;T854=;Q1463=] allele linked to haplotype 1–2–21–6–17–13 – 2.2% in F508del chromosomes. No differences in disease severity in patients carrying complex allele [L467F;F508del] and patients homozygous for F508del was found.ConclusionThe frequency of complex alleles associated with F508del was at least 6.6% in Russian CF patients, which should be taken into account for the decision on optimal treatment options with CFTR modulators.

Congenital aniridia (AN) is a severe autosomal dominant panocular disorder associated with pathogenic variants in the PAX6 gene. Previously, we performed a molecular genetic study of a large cohort of Russian patients with AN and revealed four noncoding nucleotide variants in the PAX6 5'UTR. 14 additional PAX6-5'UTR variants were also reported in the literature, but the mechanism of their pathogenicity remained unclear. In the present study, we experimentally analyze five patient-derived PAX6 5'UTR-variants: four variants that we identified in Russian patients (c.-128-2delA, c.-125dupG, c.-122dupG, c.-118_-117del) and one previously reported (c.-52+5G>C). We show that the variants lead to a decrease in the protein translation efficiency, while mRNA expression level is not significantly reduced. Two of these variants also affect splicing. Furthermore, we predict and experimentally validate the presence of an evolutionarily conserved small uORF in the PAX6 5'UTR. All studied variants lead to the frameshift of the uORF, resulting in its extension. This extended out-of-frame uORF overlaps with the downstream CDS and thereby reduces its translation efficiency. We conclude that the uORF frameshift may be the main mechanism of pathogenicity for at least 15 out of 18 known PAX6 5'UTR variants. Moreover, we predict additional uORFs in the PAX6 5'UTR.

Orphan diseases is a significant socio-economic burden for both global and Russian health care systems. The global burden of disease metrics introduced by WHO, such as DALY, QALY, HALE, can be a useful tool for building economic models and prognoses, as well as medicine funding distribution. However, it is very difficult to standardize a heterogeneous group of rare diseases and it is difficult to talk about the cost-effective treatment options search, in cases where patients with an orphan disease may have only one pathogenetic therapy option. Much work needs to be done to find optimal treatment options and establish the standards of care necessary to maintain physical health, work capacity and quality of life.

Hereditary nonsyndromic sensorineural hearing loss is a disease in which hearing loss occurs due to damage to the organ of the inner ear, the auditory nerve, or the center in the brain that is responsible for the perception of sound, characterized by wide locus and allelic heterogeneity and different types of inheritance. Given the diversity of population of the Russian Federation, it seems necessary to study the ethnic characteristics of the molecular causes of the disease. The aim is to study the molecular and genetic causes of hereditary sensorineural hearing loss in Chuvash, the fifth largest ethnic group in Russia. DNA samples of 26 patients from 21 unrelated Chuvash families from the Republic of Chuvashia, in whom the diagnosis of hereditary sensorineural hearing loss had been established, were analyzed using a combination of targeted Sanger sequencing, multiplex ligase-dependent probe amplification, and whole exome sequencing. The homozygous variant NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) is the major molecular cause of hereditary sensorineural hearing loss in 23% of Chuvash patients (OMIM #601869). Its frequency was 25% in patients and 1.1% in healthy Chuvash population. Genotyping of the NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) variant in five neighboring populations from the Volga-Ural region (Russian, Udmurt, Mary, Tatar, Bushkir) found no evidence that this variant is common in those populations.

Hereditary nonsyndromic sensorineural hearing loss is a disease in which hearing loss occurs due to damage to the organ of the inner ear, the auditory nerve, or the center in the brain that is responsible for the perception of sound, characterized by wide locus and allelic heterogeneity and different types of inheritance. Given the diversity of population of the Russian Federation, it seems necessary to study the ethnic characteristics of the molecular causes of the disease. The aim is to study the molecular and genetic causes of hereditary sensorineural hearing loss in Chuvash, the fifth largest ethnic group in Russia. DNA samples of 26 patients from 21 unrelated Chuvash families from the Republic of Chuvashia, in whom the diagnosis of hereditary sensorineural hearing loss had been established, were analyzed using a combination of targeted Sanger sequencing, multiplex ligase-dependent probe amplification, and whole exome sequencing. The homozygous variant NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) is the major molecular cause of hereditary sensorineural hearing loss in 23% of Chuvash patients (OMIM #601869). Its frequency was 25% in patients and 1.1% in healthy Chuvash population. Genotyping of the NM_133261.3(GIPC3):c.245A>G (p.Asn82Ser) variant in five neighboring populations from the Volga-Ural region (Russian, Udmurt, Mary, Tatar, Bushkir) found no evidence that this variant is common in those populations.

Cystic fibrosis (CF) is the most common monogenic autosomal recessive disease, associated with pathogenic variants in the CFTR gene. The splicing variant c.3140-16T>A (3272-16T>A) has been described previously and, according to the Russian CF Patients Registry, occurs with a frequency of 0.34%. The phenotypic features of CF patients with the c.3140-16T>A variant were compared with those of patients with the genotype F508del/F508del. Patients with the allele c.3140-16T>A had higher average age and age at diagnosis, and the allele was present in a greater proportion of adults. Patients carrying the c.3140-16T>A allele were characterised by better physical development indicators, both in adults and in children, had preserved pancreatic function, as well as the absence of a number of complications, and required pancreatic enzyme replacement therapy less often than patients with the F508del/F508del genotype. Sweat test values also were lower in patients with the c.3140-16T>A genotype. According to the results of clinical and laboratory studies, the phenotype of patients with the genetic variant c.3140-16T>A can be considered “mild”. Functional CFTR protein activity in the presence of c.3140-16T>A was evaluated using intestinal current measurements (ICM) and the forskolin-induced swelling assay on organoids obtained from patients’ rectal biopsies. c.3140-16T>A had high residual CFTR channel activity and was amenable to effective pharmacological correction with thea VX-770 potentiator. To evaluate the effect of the variant on CFTR pre-mRNA splicing we performed a minigene assay, as well as RT-PCR analysis of RNA isolated from the nasal epithelium and rectal biopsy of patients. We showed that the c.3140-16T>A variant creates a novel acceptor AG dinucleotide within CFTR intron 19, resulting in a 14-nucleotide extension of exon 20. This frameshift produces a premature termination codon and triggers mRNA degradation by the nonsense-mediated decay (NMD) mechanism. Moreover, we observed that the c.3140-16T>A allele could produce a residual amount of normally spliced transcript, thus explaining the patient’s mild phenotype.

Genome-wide sequencing metadata allows researchers to infer bias in the relative frequencies of mutational events and to predict putative mutagenic models. In addition, much less data could be useful in the evaluation of the mutational frequency spectrum and the prevalent local mutagenic process. Here we analyzed the PAX6 gene locus for mutational spectra obtained in our own and previous studies and compared them with data on other genes as well as the whole human genome. MLPA and Sanger sequencing were used for mutation searching in a cohort of 199 index patients from Russia with aniridia and aniridia-related phenotypes. The relative frequencies of different categories of PAX6 mutations were consistent with those previously reported by other researchers. The ratio between substitutions, small indels, and chromosome deletions in the 11p13 locus was within the interval previously published for 20 disease associated genomic loci, but corresponded to a higher end due to very high frequencies of small indels and chromosome deletions. The ratio between substitutions, small indels, and chromosome deletions for disease associated genes, including the PAX6 gene as well as the share of PAX6 missense mutations, differed considerably from those typical for the whole genome.

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.

The spinal muscular atrophy is neuromuscular disease caused by mutations in SMN1 gene. The clinical picture of disease is characterized by progressive muscular weakness and atrophy associated with degeneration of spine, and in severe cases by affection of motor neurons of lower bulbar cells. The spinal muscular atrophy progressing course resulting in disability and infant mortality. Actually, specific treatment is at the stage of clinical trials. However, patients are needed in permanent symptomatic arresting of manifestations and pathogenetic treatment preventing development of disease. The article presents calculations of direct medical costs for treatment in pediatric patients (0-17 years old) in Moscow with the main types of spinal muscular atrophy. It is established that the cost of specialized medical care of children with spinal muscular atrophy per single under age patient in Moscow consisted 7,131,185.84 rubles annually, including primary diagnostic, treatment and rehabilitation and medicinal treatment. In total, according to data for 2020 in Moscow, where number of children patients is 144, the cost of specialized medical care of children with spinal muscular atrophy is estimated as 1,024,580,269.16 rubles. At that, data takes into account only direct medical costs for out-patient and in-patient care of children with spinal muscular atrophy, excluding number of exacerbations of disease. Taking into account average numbers of hospitalizations per year because of illness, the cost of in-patient care of single child amounts to 7,844,304.42 rubles annually and 1,127,018,732.08 rubles for all children with spinal muscular atrophy in Moscow (according data of 2020).

Background: Recently, there has been an increasing interest in understanding the ethnic differences in genetic risk factors associated with childhood asthma. Aim: to analyze the association of GSDMB, NOS1, NOS2, NOS3, ADRB2, FCER2, TNFA, GSTM1 genes with the development of asthma. To identify markers of increased risk in Buryat adolescents living in the Zabaykalsky Kray depending on their gender. 10 single-nucleotide polymorphisms (SNP) in studied genes were genotyped in 68 Buryat asthmatics, and 100 healthy. In the male group: 31 asthmatics, and 54 healthy. In the female group: 37, and 46 respectively. Results: The diagnosis of asthma was associated with GSDMB(rs7216389), NOS1(AAT)n and (VNTR). Markers of disease increased risk include: the homozygous genotype TT of the rs7216389 GSDMB (p A) are considered risk factors; while in boys, alleles containing long repeats of L and LL genotypes NOS1 (AAT)n predispose to asthma. Conclusion: We identified 4 SNPs associated with asthma in Buryats adolescents: (AAT)n predispose to asthma.

Background: Asthma is a complex disease resulting from interactions between multiple genes and environmental factors. Objective: We investigated gene-gene interactions and asthma risk in Buryats. 10 SNPs of 8 genes possibly associated with asthma were tested in 68 Buryat asthmatics and 100 controls. Gene-gene interactions were analyzed by generalized multifactor dimensionality reduction (GMDR, MDR). Results: 4 models of gene-gene interactions predisposing to the development of asthma in Buryats were revealed. (rs7216389), ADRB2 (Arg16Gly), ADRB (Gln27Glu), NOS1 (AAT)n with a cross-validation interval (CV) consistency 10/10 (p=0.001), balanced accuracy 0,8397, balanced accuracy 0,7593; GSDMB (rs7216389), ADRB2(Arg16Gly), NOS1(AAT)n with a CV consistency of 9/10 (p=0.001). Optimal models of gene-gene interactions were GSDMB (rs7216389), FCER(T2206C) with a CV consistency of 5/10 (p=0.001); GSDMB (rs2305480), GSDMB rs7216389), FCER(T2206C), ADRB2(Arg16Gly), NOS2А(CCTTT)n, NOS1 (AAT)n with a CV consistency 6/10 (p=0.01). For each model of gene-gene interactions, we compared the frequency of genotypes of interacting genes in asthma patients and in healthy controls. Genotypes of increased risk of asthma developing in Buryats were GSDMB rs7216389*TТ - ADRB2(Arg16Gly)*АG - (T2206C)*TT (p Conclusions: The study showed that it is necessary to take into account gene-gene interactions when predicting the risk of asthma developing. Conclusions: The study showed that it is necessary to take into account gene-gene interactions when predicting the risk of asthma developing.

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

The article considers the results of legal regulation analysis of medical care support including medication maintenance of adult patients suffering from rare diseases exemplified by life-threatened and chronic progressed rare (orphan) diseases resulting in life expectancy decrease and or disability (“List-24”). Materials and methods. Law database was analyzed in terms of current orders of medical care provision, standards of medical care, and clinical guidelines for rare diseases from “List-24” regarding to adult patients. Results. It is concluded that there are no determined rules of medical care provision to adult population in case of rare diseases from “List-24”. There are standards of medical care on 6 rare diseases (25% of total diseases amount) from this list for adult patients. However, based on content analysis data of approved standards it was established that there are only 3 from 11 standards (27.28%) for primary medical care support, 4 standards (33.34%) for medical care provision in planned condition, and only 1 standard (9.09%) had appropriate legal basis for its development (clinical guidelines availability). Nevertheless, there is negative prognosis for this the only standard due to legal necessity of all clinical guidelines revision till the end of 2021. Conclusion. Revision and creation of clinical guidelines and standards of medical care afterwards are needed for adult patients treatment with rare diseases from “List-24”. The conclusion was made in terms of medical care standardization improvement for adult patients suffering from rare diseases from “List-24” based on its alignment with current legal regulation.

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.