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

The significant variability in the clinical manifestations of COL2A1-associated skeletal dysplasias makes it necessary to conduct a clinical and genetic analysis of individual nosological variants, which will contribute to improving our understanding of the pathogenetic mechanisms and prognosis. We presented the clinical and genetic characteristics of 60 Russian pediatric patients with type II collagenopathies caused by previously described and newly identified variants in the COL2A1 gene. Diagnosis confirmation was carried out by new generation sequencing of the target panel with subsequent validation of the identified variants using automated Sanger sequencing. It has been shown that clinical forms of spondyloepiphyseal dysplasias predominate in childhood, both with more severe clinical manifestations (58%) and with unusual phenotypes of mild forms with normal growth (25%). However, Stickler syndrome, type I was less common (17%). In the COL2A1 gene, 28 novel variants were identified, and a total of 63% of the variants were found in the triple helix region resulted in glycine substitution in Gly-XY repeats, which were identified in patients with clinical manifestations of congenital spondyloepiphyseal dysplasia with varying severity, and were not found in Stickler syndrome, type I and Kniest dysplasia. In the C-propeptide region, five novel variants leading to the development of unusual phenotypes of spondyloepiphyseal dysplasia have been identified.

Multiple epiphyseal dysplasias (MED) are a clinically and genetically heterogeneous group of skeletal dysplasias with a predominant lesion in the epiphyses of tubular bones. Variants in the SLC26A2 gene cause their autosomal recessive form (rMED or MED type 4). The accumulation of data regarding the genotype–phenotype correlation can help in the diagnosis and proper management of these patients. The aim of this study was to survey the clinical and genetic characteristics of 55 patients with MED type 4 caused by variants in the SLC26A2 gene. Diagnosis confirmation was carried out by radiography and custom panel sequencing consisting of 166 genes responsible for the development of hereditary skeletal pathology. This was followed by the validation of the identified variants using automated Sanger sequencing (for six patients) and the direct automatic Sanger sequencing of the coding sequence and the adjacent intron regions of the SLC26A2 gene for 49 patients. Based on the clinical and genetic analysis of our sample of patients, two main MED type 4 phenotypes with early and late clinical manifestations were identified. An early and more severe form of the disease was observed in patients with the c.835C > T variant (p.Arg279Trp), and the late and milder form of the disease was observed in patients with the c.1957T > A variant (p.Cys653Ser) in the homozygous or compound heterozygous state with c.26 + 2T > C. It was also shown that only three pathogenic variants were found in 95.3% of the alleles of Russian patients with MED type 4: c.1957T > A (p.Cys653Ser), c.835C > T (p.Arg279Trp), and c.26 + 2T > C; thus, it can be assumed that the primary analysis of these variants will contribute to the optimal molecular genetic diagnostics of MED type 4.

GNE myopathy (GNEM) is a rare hereditary disease, but at the same time, it is the most common distal myopathy in several countries due to a founder effect of some pathogenic variants in the GNE gene. We collected the largest cohort of patients with GNEM from Russia and analyzed their mutational spectrum and clinical data. In our cohort, 10 novel variants were found, including 2 frameshift variants and 2 large deletions. One novel missense variant c.169_170delGCinsTT (p.(Ala57Phe)) was detected in 4 families in a homozygous state and in 3 unrelated patients in a compound heterozygous state. It was the second most frequent variant in our cohort. All families with this novel frequent variant were non-consanguineous and originated from the 3 neighboring areas in the European part of Russia. The clinical picture of the patients carrying this novel variant was typical, but the severity of clinical manifestation differed significantly. In our study, we reported two atypical cases expanding the phenotypic spectrum of GNEM. One female patient had severe quadriceps atrophy, hand joint contractures, keloid scars, and non-classical pattern on leg muscle magnetic resonance imaging, which was more similar to atypical collagenopathy rather than GNEM. Another patient initially had been observed with spinal muscular atrophy due to asymmetric atrophy of hand muscles and results of electromyography. The peculiar pattern of muscle involvement on magnetic resonance imaging consisted of pronounced changes in the posterior thigh muscle group with relatively spared muscles of the lower legs, apart from the soleus muscles. Different variants in the GNE gene were found in both atypical cases. Thus, our data expand the mutational and clinical spectrum of GNEM.

Background: Spastic paraplegia type 30 (SPG30) caused by KIF1A mutations was first reported in 2011 and was initially considered a very rare autosomal recessive (AR) form. In the last years, thanks to the development of massive parallel sequencing, SPG30 proved to be a rather common autosomal dominant (AD) form of familial or sporadic spastic paraplegia (SPG),, with a wide range of phenotypes: pure and complicated. The aim of our study is to detect AD SPG30 cases and to examine their molecular and clinical characteristics for the first time in the Russian population. Methods: Clinical, genealogical and molecular methods were used. Molecular methods included massive parallel sequencing (MPS) of custom panel ‘spastic paraplegias’ with 62 target genes complemented by familial Sanger sequencing. One case was detected by the whole -exome sequencing. Results: AD SPG30 was detected in 10 unrelated families, making it the 3rd (8.4%) most common SPG form in the cohort of 118 families. No AR SPG30 cases were detected. In total, 9 heterozygous KIF1A mutations were detected, with 4 novel and 5 known mutations. All the mutations were located within KIF1A motor domain. Six cases had pure phenotypes, of which 5 were familial, where 2 familial cases demonstrated incomplete penetrance, early onset and slow relatively benign SPG course. All 4 complicated cases were caused by novel mutations without familial history. The phenotypes varied from severe in two patients (e.g. lack of walking, pronounced mental retardation) to relatively mild non-disabling symptoms in two others. Conclusion: AD SPG30 is one of the most common forms of SPG in Russia, the disorder has pronounced clinical variability while pure familial cases represent a significant part.