Population allele frequency is crucially important for accurate interpretation of known and novel variants in medical genetics. Recently, several large allele frequency databases, such as the Genome Aggregation Database (gnomAD), have been created to serve as a global reference for such studies. However, frequencies of many rare alleles vary dramatically between populations, and population-specific allele frequency is often more informative than the global one. Many countries and regions, including Russia, remain poorly studied from the genetic perspective. Here, we report the first successful attempt to integrate genetic information between major medical genetic laboratories in Russia. We construct RUSeq, an open, large-scale reference set of genetic variants by analyzing 7452 exome samples collected in two major Russian cities-Moscow and St. Petersburg. An similar to 10-fold increase in sample size compared to previous studies allowed us to characterize extensive genetic diversity within the admixed Russian population with contributions from several major ancestral groups. We highlight 51 known pathogenic variants that are overrepresented in Russia compared to other European countries. We also identify several dozen high-impact variants that are present in healthy donors despite being annotated as pathogenic in ClinVar and falling within genes associated with autosomal dominant disorders.

Background. Desmoid fibromatosis (DF) is a rare mesenchymal tumor with invasive growth, a high relapse rate, and low incidence (24 cases per 1 million people per year). Given the small number of patients with DF and, as a result, the lack of knowledge of this disease, the search for molecular predictors of the disease course and the individualization of treatment and prevention is relevant. Aim. To study tumor cells' molecular genetic and immunohistochemical profile and determine their clinical significance in patients with abdominal and retroperitoneal DF. Materials and methods. A comprehensive analysis of clinical and laboratory data of 31 patients with abdominal and retroperitoneal DF, a molecular genetic and morphological study of tumor samples was performed, including next-generation sequencing (NGS) using the Onconetix oncology panel and an immunohistochemical study using antibodies to -catenin and estrogen and progesterone receptors. Results. NGS testing showed somatic mutations in 28 (90%) of the 31 tumor samples. Somatic mutations in the CTNNB1 gene were detected in 26 (84%) tumor samples: 21 (68%) patients had c.121AG (p.Thr41Ala, rs121913412), 3 (10%) patients had c.134CT (p.Ser45Phe, rs121913409), 1 (3%) patient had c.133TC (p.Ser45Pro, rs121913407), and 1 (3%) patient had c.122CT (p.Thr41Ile, rs121913413). Two (6%) patients had mutations in the APC gene: c.4381GT (p.Glu1461Ter, COSM30779) and c.4634CA (p.Ser1545Ter, rs863225356). In 3 (9%) patients, no mutations were detected in the studied genes. The immunohistochemical study showed the expression of -catenin in the cytoplasm and nuclei of tumor cells in 16 (51.6%) samples. Nuclear expression of estrogen and progesterone receptors was detected in 6 (19%) and 1 (3.2%) samples, respectively. Of 10 patients with established relapses, sequencing (NGS) showed a c.121AG mutation (p.Thr41Ala, rs121913412) in 7; 1 patient had a c.134CT mutation (p.Ser45Phe, rs121913409), and 2 patients had no mutations in tumor samples. Conclusion. The combination of factors such as the retroperitoneal DF, the presence of the c.121AG mutation (p.Thr41Ala, rs121913412) in the CTNNB1 gene, female gender, and young age, can warrant assigning the patient to the group with an unfavorable DF prognosis.

Population allele frequency is crucially important for accurate interpretation of known and novel variants in medical genetics. Recently, several large allele frequency databases, such as Genome Aggregation Database (gnomAD), have been created to serve as a global reference for such studies. However, frequencies of many rare alleles vary dramatically between populations, and population-specific allele frequency is often more informative than the global one. Many countries and regions, including Russia, remain poorly studied from the genetic perspective. Here, we report the first successful attempt to integrate genetic information between major medical genetic laboratories in Russia. We construct an open, large-scale reference set of genetic variants by analyzing 7,492 exome samples collected in two major Russian cities of Moscow and St. Petersburg. An approximately tenfold increase in sample size compared to previous studies allowed us to identify genetically distinct clusters of individuals within an admixed population of Russia. We highlight 47 known pathogenic variants that are overrepresented in Russia compared to other European countries. We also identify several dozen high-impact variants that are present in healthy donors despite either being annotated as pathogenic in ClinVar or falling within genes associated with autosomal dominant disorders. The constructed database of genetic variant frequencies in Russia has been made available to the medical genetics community through a variant browser available at . ### Competing Interest Statement Analysis of NGS data and the construction of the catalogue of allele frequencies was funded jointly by the Genetics and Reproductive Medicine Center GENETICO Ltd. and CerbaLab Ltd. according to the partnership agreement dated 25.10.2021. All rights to the data and resources generated during the work are reserved to the aforementioned parties. ### Funding Statement The work was supported by the Systems Biology Fellowship to Y.A.B. the Presidential Fellowship for Young Scientists (grant no. SP-4503.2021.4) to Y.A.B., and D.O. Ott Research Institute of Obstetrics, Gynaecology and Reproductology, project 558-2019-0012 (AAAA-A19119021290033-1) of FSBSI. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the ethics committee of the D.O. Ott Institute of Obstetrics, Gynecology, and Reproductology (protocol 114 from 14 December 2021) and conducted in accordance with the Declaration of Helsinki. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes Variant frequency level data produced in the present study are available via form submission available at ruseq.ru.

Jansen-de Vries syndrome is a rare hereditary autosomal dominant disease caused by pathogenic variants in the PPM1D gene. To date, 18 cases of this syndrome have been described in the world. In all cases, heterozygous mutations were identified that arose de novo in the last or penultimate exons of the gene, leading to protein truncation. All observed patients had muscle hypotonia, delayed motor and speech development, intellectual and behavioral disorders, an increased pain threshold, and a peculiar phenotype. Objective of the research: to reveal clinical genetic signs of new cases of a rare syndromic form and to identify additional clinical and laboratory features that characterize Jansen-de Vries syndrome. The article presents observations of two patients with Jansen-de Vries syndrome, first diagnosed in the Russian Federation. Children underwent routine laboratory and instrumental examinations, repeated consultations with a neurologist, geneticist, ophthalmologist, cardiologist and orthopedist. The diagnosis was made by full exome sequencing. A comparison of the identified cases with those described in the literature is performed. The observed girls from two unrelated families showed characteristic clinical manifestations, as in patients previously presented in the foreign literature: muscle hypotension, delayed motor and psycho-speech development, small hands and feet. Additionally, the first child had a prolonged course of neonatal meningitis and a low level of immunoglobulin A, the second had unilateral ptosis, congenital stridor. The de novo mutations found were confirmed by Sanger sequencing. A previously undescribed pathogenic variant c.1225del (p.Met409Ter) in the penultimate exon of the PPM1D gene was detected in the first child of 10 months. In the second child, a previously established pathogenic variant c.1270dupG (p.Glu424fs) was found in the last exon of this gene. Conclusion: the work presents the first domestic observations confirming the presence of characteristic clinical and genetic manifestations of the Jansen-de Vries syndrome. In addition, a previously undescribed pathogenic variant c.1225del (p.Met409Ter) was revealed in the penultimate exon of the PPM1D gene. In one of the observed children, features of humoral immunity were found, which may also be characteristic of this pathology.

The frequency of a genetic variant in a population is crucially important for accurate interpretation of known and novel variant effects in medical genetics. Recently, several large allele frequency databases, such as Genome Aggregation Database (gnomAD), have been created to serve as a global reference for such studies. However, frequencies of many rare alleles vary dramatically between populations, and population-specific allele frequency can be more informative than the global one. Many countries and regions (including Russia) remain poorly studied from the genetic perspective. Here, we report the first successful attempt to integrate genetic information between major medical genetic laboratories in Russia. We construct an expanded reference set of genetic variants by analyzing 6,096 exome samples collected in two major Russian cities of Moscow and St. Petersburg. An approximately tenfold increase in sample size compared to previous studies allowed us to identify genetically distinct clusters of individuals within an admixed population of Russia. We show that up to 18 known pathogenic variants are overrepresented in Russia compared to other European countries. We also identify several dozen high-impact variants that are present in healthy donors despite either being annotated as pathogenic in ClinVar or falling within genes associated with autosomal dominant disorders. The constructed database of genetic variant frequencies in Russia has been made available to the medical genetics community through a variant browser available at http://ruseq.ru.

Изучение спектра мутаций и совершенствование диагностики синдрома Ашера (СА) особо актуальны в связи с разрабатываемыми подходами к генной терапии заболевания. Среди 46 пациентов с признаками СА патогенные мутации выявлены нами у 40 (87%) пациентов. СА I и II типов определены у 26% и 57% пробандов исходной выборки, соответственно. У пациентов с СА I выявлены мутации в генах MYO7A (73%), CDH23 (7%), PCDH15 (7%), и USH1C (13%). Наибольшую частоту показала мутация MYO7A p.Q18*. Описано 6 новых мутаций в гене MYO7A, и две - в гене PCDH15. У пациентов с СА II выявлена 21 мутация гена USH2A, 5 из которых описаны впервые. Наибольшую частоту показала мутация USH2A p.W3955*. У двух пациентов выявлены мутации в генах несиндромального пигментного ретинита RHO и RPGR, что позволило уточнить клинический диагноз. Studying the mutation spectrum and improvement of molecular verification of the Usher syndrome (USH) are of particular relevance as gene therapy emerges. Among 46 patients with signs of Usher syndrome we identified mutations in 40 (85%) patients, establishing a diagnosis of USH1 and USH2 for 26% and 57% of the probands of the initial sample, respectively. Patients with USH1 showed mutations in the MYO7A (73%), CDH23 (7%), PCDH15 (7%), and USH1C (13%) genes. MYO7A p.Q18* mutation showed the highest frequency. We have identified 6 new mutations in the MYO7A gene, and 2 in the PCDH15 gene. In USH2 patients, 21 USH2A gene mutations were identified, 5 of which are novel. The USH2A mutation p.W3955* was most frequent. Two patients showed mutations in the non-syndromic retinitis pigmentosa genes RHO and RPGR, which made it possible to clarify the clinical diagnosis.