Background/Objectives: According to the International Classification of Hereditary Skeletal Diseases (2019), osteogenesis imperfecta (OI) is classified as a disorder resulting from impaired formation of the cortical layer density of diaphyses and metaphyseal modeling. OI comprises a heterogeneous group of genetic diseases, with most cases inherited in an autosomal dominant manner, while others follow autosomal recessive or X-linked recessive inheritance patterns. Accurate DNA testing is essential for precise medical and genetic counseling, ensuring reliable prognostic assessments for patients’ descendants and siblings. As part of a medical genetic study of the population of the Republic of the North Ossetia Alania, specifically in the Mozdok district, specialists from the Laboratory of Genetic Epidemiology at the Research Centre for Medical Genetics (RCMG) examined a family with 13 affected individuals with OI across four generations. Methods: A comprehensive clinical assessment was performed, followed by molecular genetic analysis using whole-exome sequencing (WES). Segregation analysis within the family was conducted via Sanger sequencing. Results: Clinical evaluation suggested a diagnosis of OI, which was subsequently confirmed by genetic testing. The severity and spectrum of symptoms varied considerably among affected family members and were influenced by age and specific nuclear family lineage. Molecular analysis in the proband identified a heterozygous pathogenic variant in the COL1A1 gene variant (c.1243C>T, p.(Arg415*)), confirming a diagnosis of OI type IV. The variant was found to co-segregate with the disease within the family. Conclusions: Molecular diagnosis enabled precise risk assessment for affected offspring in family members with mild phenotypic manifestations. Additionally, pediatric patients were referred for standard bisphosphonate therapy to manage the condition effectively.

Background: A number of association studies have linked ribosomal DNA gene copy number (rDNA CN) to aging and pathology. Data from these studies are contradictory and depend on the quantitative method. Methods: The hybridization technique was used for rDNA quantification in human cells. We determined the rDNA CN from healthy controls (HCs) and patients with schizophrenia (SZ) or cystic fibrosis (CF) (total number of subjects N = 1124). For the first time, rDNA CN was quantified in 105 long livers (90–101 years old). In addition, we conducted a joint analysis of the data obtained in this work and previously published by our group (total, N = 3264). Results: We found increased rDNA CN in the SZ group (534 ± 108, N = 1489) and CF group (567 ± 100, N = 322) and reduced rDNA CN in patients with mild cognitive impairment (330 ± 60, N = 93) compared with the HC group (422 ± 104, N = 1360). For the SZ, CF, and HC groups, there was a decreased range of rDNA CN variation in older age subgroups compared to child subgroups. For 311 patients with SZ or CF, rDNA CN was determined two or three times, with an interval of months to several years. Only 1.2% of patients demonstrated a decrease in rDNA CN over time. We did not find significant rDNA CN variation in eight different organs of the same patient or in cells of the same fibroblast population. Conclusions: The results suggest that rDNA CN is a relatively stable quantitative genetic trait statistically associated with some diseases, which however, can change in rare cases under conditions of chronic oxidative stress. We believe that age- and disease-related differences between the groups in mean rDNA CN and its variance are caused by the biased elimination of carriers of marginal (predominantly low) rDNA CN values.

BACKGROUND:Newborn screening (NBS) for severe combined immunodeficiency (SCID) relies on the measurement of T-cell receptor excision circle (TREC) for early diagnosis and intervention. However, considerable variation in TREC cutoff values across countries and testing platforms poses challenges for standardization and optimal screening performance. This study aimed to refine the TREC cutoff values in a large Russian pilot NBS cohort comprising 202,908 newborns, with a primary focus on improving SCID detection sensitivity. METHODS:A retrospective analysis of 202,908 newborns from a pilot NBS project assessed TREC and KREC levels. Confirmed PID diagnoses were compared with TREC measurements in a group of 66 false-positive cases. The optimal TREC cutoff was established using ROC analysis, with validation across patients with SCID, 22q11.2 deletion syndrome (22q11.2DS), and syndromic forms of PID from an extended validation cohort of PID patients from the Dmitry Rogachev National Medical Research Center. RESULTS:Receiver operating characteristic (ROC) analysis based on true-positive cases identified an optimal TREC cutoff of 150 copies/105 cells. Values between 150-200 copies/105 cells were found to identify high-risk newborns who require closer monitoring. This threshold was validated in an independent cohort, reducing missed SCID cases while improving the detection of 22q11.2 deletion syndrome and other syndromic primary immunodeficiencies (PIDs). Notably, elevated TREC levels in some SCID patients reflected "leaky" SCID phenotypes, which nonetheless required curative intervention. Additionally, syndromic PIDs and cases of transient idiopathic lymphopenia (TIL) were also more accurately identified, enabling timely clinical management. CONCLUSION:These findings emphasize the need for broader evaluation of TREC cutoff values across diverse assay systems to improve the effectiveness, comparability, and global harmonization of NBS programs.

This study investigates a unique and complex eye phenotype characterized by minimal iris defects, foveal hypoplasia, optic nerve coloboma, and severe posterior segment damage. Through genetic analysis and bioinformatic tools, a specific nonsynonymous substitution, p.(Asn114Ser), within the PAX6 gene's paired domain is identified. Although this substitution is not in direct contact with DNA, its predicted stabilizing effect on the protein structure challenges the traditional understanding of PAX6 mutations, suggesting a gain-of-function mechanism. Contrary to classical loss-of-function effects, this gain-of-function hypothesis aligns with research demonstrating PAX6's dosage sensitivity. Gain-of-function mutations, though less common, can lead to diverse phenotypes distinct from aniridia. Our findings emphasize PAX6's multifaceted influence on ocular phenotypes and the importance of genetic variations. We contribute a new perspective on PAX6 mutations by suggesting a potential gain-of-function mechanism and showcasing the complexities of ocular development. This study sheds light on the intricate interplay of the genetic alterations and regulatory mechanisms underlying complex eye phenotypes. Further research, validation, and collaboration are crucial to unravel the nuanced interactions shaping ocular health and development.

Sovremennye znaniya o kumulyativnoj rasprostranennosti, raznoobrazii i chastote vstrechaemosti otdel'nyh orfannyh nasledstvennyh boleznej (ONB) sredi detskogo naseleniya ogranicheny v RF i mirovyh issledovaniyah nesmotrya na shirokuyu vostrebovannost' dlya zdravoohraneniya i obshchestva. Dlya ONB harakterny izmenchivost' i neodnorodnost' vysheperechislennyh pokazatelej dlya raznyh populyacij, kotoraya takzhe proyavlyaetsya v shirokoj geneticheskoj geterogennosti. Cel'yu raboty bylo izuchenie ONB sredi detskogo naseleniya Respubliki Severnaya Osetiya – Alaniya (RSO-A). Obsledovano 543 817 chelovek, v tom chisle 145560 detej (ot 0 do 18 let). Rasschitana kumulyativnaya rasprostranennost' autosomno-recessivnoj (AR), autosomno-dominantnoj (AD) i H-sceplennoj (H-sc.) nasleduemoj patologii. Po poluchennym rezul'tatam, summarnaya rasprostranennost' ONB sredi detej RSO-A sostavlyaet 1 : 119, t. e. 1% detej imeet diagnoz ONB. V sel'skoj mestnosti summarnaya otyagoshchennost' detskogo naseleniya vsemi tipami ONB bolee chem v 2 raza vyshe, chem v gorodah i rajonnyh centrah. Vyyavlen 1241 pacient (iz 1037 semej) s 241 nozologicheskoj formoj ONB (109 form — s AD-nasledovaniem, 102 — s AR i 30 — s H-sc.). Osobennost'yu obsledovannoj populyacii yavlyaetsya vysokaya rasprostranennost' trekh zabolevanij, ranee ne ustanovlennyh v podobnyh issledovaniyah: vrozhdennaya miasteniya 12-go tipa, redkaya forma vrozhdennoj disfunkcii kory nadpochechnikov — deficit 3-beta-gidroksisteroiddegidrogenazy, sindrom brahidaktilii tipa E — amelogeneza — umstvennoj otstalosti — nanizma. Takim obrazom, naselenie RSO-A harakterizuetsya specificheskim spektrom ONB, obuslovlennyh redkimi mutaciyami, chast' iz kotoryh redko vstrechaetsya v drugih populyaciyah mira i RF. Obrashchaet na sebya vnimanie bolee vysokaya rasprostranennost' dannogo spektra patologij v sel'skih populyaciyah. Vyyavlennye pokazateli svidetel'stvuyut o neobhodimosti razrabotki specializirovannyh region-specificheskih programm dlya profilaktiki detskoj invalidnosti i/ili letal'nosti.

This study, conducted in the Republic of North Ossetia-Alania (RNOA), aimed to explore the genetic landscape of hyperphenylalaninemia (HPA) and phenylketonuria (PKU) in the Ossetian population using data from newborn screening (NBS). Through comprehensive molecular genetic analysis of 29 patients with HPA from diverse ethnic backgrounds, two major genetic variants in the PAH gene, P281L and P211T, were identified, constituting 50% of all detected pathogenic alleles in Ossetian patients. Remarkably, these variants exhibited an exceptionally high frequency in the Ossetian population, surpassing global prevalence rates. This study unveiled a notable prevalence of mild forms of HPA (78%), underscoring the importance of genetic counseling for carriers of pathogenic variants in the PAH gene. Moreover, the findings emphasized the necessity for ongoing monitoring of patients with mild forms, as they may lack significant symptoms for diagnosis, potentially impacting offspring. Overall, this research offers valuable insights into the genetic landscape of HPA and PKU in the Ossetian population.

The expanded newborn screening (NBS) program in the Russian Federation was initiated in 2023, among which severe combined immunodeficiency (SCID) is screened using TREC/KREC assays. Here, we report a rare case of a TP63-associated disease identified through this NBS program. Dried blood spots from newborns were initially screened for TREC/KREC levels, and those with values below the cut-off underwent confirmatory testing and further genetic analysis, including whole-exome sequencing (WES). A male newborn was identified with significantly reduced TREC values, indicative of T cell lymphopenia. Genetic analysis revealed a heterozygous NM_003722.5:c.1027C>T variant in TP63, leading to the p.(Arg343Trp) substitution within the DNA binding domain. This mutation has been previously associated with Ectrodactyly–Ectodermal Dysplasia–Cleft lip/palate syndrome (EEC) syndrome and shown to reduce the transactivation activity of TP63 in a dominant-negative manner. This case represents one of the few instances of immune system involvement in a patient with a TP63 mutation, highlighting the need for further investigation into the immunological aspects of TP63-associated disorders. Our findings suggest that comprehensive immunological evaluation should be considered for patients with TP63 mutations to better understand and manage potential immune dysfunctions.

Newborn screening (NBS) for severe inborn errors of immunity (IEI), affecting T lymphocytes, and implementing measurements of T cell receptor excision circles (TREC) has been shown to be effective in early diagnosis and improved prognosis of patients with these genetic disorders. Few studies conducted on smaller groups of newborns report results of NBS that also include measurement of kappa-deleting recombination excision circles (KREC) for IEI affecting B lymphocytes. A pilot NBS study utilizing TREC/KREC detection was conducted on 202,908 infants born in 8 regions of Russia over a 14-month period. One hundred thirty-four newborns (0.66‰) were NBS positive after the first test and subsequent retest, 41

Hermansky-Pudlak syndrome (HPS) is a rare disease inherited in the autosomal recessive mode, including 11 clinical genetic subtypes. They are associated with impaired function of the BLOC protein complex (Biogenesis of Lysosome-related Organelles Complexes), and the subunits of the AP-3 complex (adaptor protein complex). Each has its own clinical features, but they are all characterized by albinism, bleeding disorder, and visual abnormalities. Eleven patients from eight unrelated families with an incoming diagnosis of albinism were examined and novel and previously described genetic variants in HPS1, HPS6, and BLOC1S6 genes (types HPS1, HPS6, and HPS9) were found. To determine the optimal therapy and recommendations for further follow up, it is necessary to consider the entire clinical spectrum and genetic polymorphism of the disease. An interdisciplinary approach, combined with the use of non-routine diagnostic techniques such as RNA analysis, is essential for achieving accurate diagnoses in certain complex cases.

Cystic fibrosis (CF) is a genetically inherited disorder characterized by a wide range of clinical manifestations and genetic variations. This study focuses on the genetic and molecular epidemiology of CF in the Russian population, utilizing data from the national CF registry. The birth prevalence of CF in Russia has been analyzed over a span of years, revealing variations in frequency. The study delves into the genetic landscape of CFTR gene variants in Russian patients, showcasing a diverse spectrum with a predominance of severe variants, some of which are rare and distinct from global populations. A total of 233 variants have been documented, exhibiting frequencies ranging from 0.01% to 51.5%, with 47 of these variants remaining uncharted within international genetic databases. As of 2021, CFTR modulator therapy has been introduced for patients under 19 years, heightening the importance of genetic diagnosis. In 2023, more than 1,850 patients under 19 received CFTR modulator therapy. Notably, the impact of complex alleles on disease progression and response to targeted therapies is gaining recognition. Comparisons with European registries highlight distinctive features of the Russian population, such as differences in age distribution among patients. Additionally, the study emphasizes the need to ascertain clinical significance and pathogenicity of newly identified genetic variants, along with exploring their suitability for targeted therapies. The integration of genetic insights into the management of CF offers potential for enhanced personalized therapeutic interventions. In conclusion, this thorough analysis provides a comprehensive understanding of the genetic nuances within the Russian CF population. By illuminating the intricate relationship between genetic variations and disease manifestation, the study underscores the essential role of genetics in shaping therapeutic strategies and improving patient outcomes. Further research and ongoing genetic exploration are crucial for optimizing the care of individuals with CF in the era of evolving therapeutic options.

Introduction:GNE-myopathy is a distal myopathy with adult-onset and initial involvement of anterior leg compartment. A founder effect has been demonstrated for some patients from several large cohorts in different countries. Methods:In this study, we investigated the allele frequency of the c.169_170delinsTT (p.(Ala57Phe)) variant in the GNE gene (NM_001128227.3) among different ethnic populations (Mari, Tatar, and Bashkir) and estimated the age of the mutation's spread event. Results:The c.169_170delinsTT variant in the GNE gene was detected in the Mari population with an allele frequency of 0.003788 but was not found in the Tatar or Bashkir populations. The disease incidence is estimated to be 1.43 (95% CI: 0.00092-43.78) per 100,000 in the Mari population. According to our study, the estimated age of the mutation's spread is 160.46 years (95% CI: 45.55-244.14). Discussion:By comparing the information gathered with historical data on migration patterns in the Middle Volga region and estimating the age of the variant's dissemination, we propose hypotheses regarding its origin and the pathways through which it spread. In the current context of increased rate of interethnic marriages, investigating the spread of common pathogenic variants from historically isolated populations is important for molecular genetic diagnosis. This approach aids in optimizing diagnostic processes and reducing the diagnostic odyssey for patients.

Background: oculocutaneous albinism (OCA) is a hereditary impairment of skin, hair, and eye pigmentation. The most common form of albinism is autosomal recessive albinism, caused by mutations in the TYR gene, accounting for approximately 40–50% of all cases of the disease in European populations. Common hypomorphic variants in the TYR gene could lead to a mild form of albinism in a compound heterozygous state with a pathogenic variant. Methods: we examined by allele specific MLPA a cohort consisting of 118 unrelated patients with albinism and 10 parents of these patients. The control cohort consisted of 200 unexamined Russian residents. Results: the patients with albinism were divided into three groups: without pathogenic variants in the TYR gene—70 patients, with one pathogenic variant in the TYR gene—20 patients, and with two pathogenic variants in the TYR gene—28 patients. Among the 20 patients with a single heterozygous variant in the TYR gene, 15 patients had the c.575C>A p.(Ser192Tyr) variant, and 15 had the c.1205G>A p.(Arg402Gln) variant. Both the c.575C>A p.(Ser192Tyr) and c.1205G>A p.(Arg402Gln) variants were identified in 12 patients. In addition to the aforementioned variants, an intronic variant c.1185-6208A>G (rs147546939) was identified in seven patients. Conclusions: the frequencies and the number of alleles c.575A, c.1205A, and c.1185-6208G in different groups of patients and the control group were compared. In this study, we demonstrate that the complex alleles [c.575C>A p.(Ser192Tyr); c.1205G>A p.(Arg402Gln)] and [c.575C>A p.(Ser192Tyr); c.1185-6208A>G; c.1205G>A p.(Arg402Gln)] are associated with oculocutaneous albinism, which is consistent with findings from other researchers.

The genetic structure of Karachay population has been studied on the basis of analysis of ten autosomal DNA markers (diallelic and multiallelic) of the nuclear genome: CCR5∆32, ID/АСЕ, D7S23(KM19), STR/THOI, STR/FABP2, STR/IVS6aGATT(CFTR), VNTR/PAH, VNTR/DAT1, VNTR/NOS3, VNTR/APOB. The total number of the sample comprises 485 individuals who are residents of four Karachay regions: Karachaevsky, Prikubansky, Malokarachayevsky, Ust-Dzhegutinsky, and the city of Cherkessk, the capital of the Karachay-Cherkess Republic. Analysis of allele’s frequency of autosomal DNA markers in Karachay geographic subgroups shows considerable genetic differentiation between them. The highest level of genetic diversity for Karachay people on the diallelic system is set at the locus ID/АСЕ, Hobs = 0.513, and on the multiallelic system is at the locus STR/THOI, Hobs = 0.792. The average value of the observed heterozygosity per locus is 0.466, varying from 0.441 in Ust-Dzhegutinsky region to 0.503 in Cherkessk. The level of genetic differences between Karachay groups (FST = 0.007) is inside the variance defined in the previously studied peoples: Mari (FST = 0.0024), Udmurt (FST = 0.0048), Chuvash (FST = 0.006), Tatars (FST = 0.0075), and Bashkir (FST = 0.008).

Currently, there is limited understanding about the cumulative prevalence, diversity, and frequency of distinct orphan hereditary diseases (OHDs) in the pediatric population, both within the Russian Federation and in the global literature. This gap exists despite a significant demand for such knowledge in healthcare and society. Variability and heterogeneity of the above indicators are common across different populations, reflecting significant genetic heterogeneity of OHDs. The study aimed to assess OHDs in the pediatric population of the Republic of North Ossetia - Alania (RNO-A). A total of 543,817 people were evaluated, including 145,560 children aged 0-18 years. The cumulative prevalence of autosomal recessive (AR), autosomal dominant (AD), and X-linked (XL) OHDs was determined. The findings indicate an overall prevalence of OHDs among children of the RNO-A of 1 : 119, meaning that approximately 1% of children are diagnosed with these conditions. Notably, the total burden in children of all types of OHDs in rural areas exceeds that in urban areas and district centers by more than twofold. We identified 1,241 patients from 1,037 families with 241 distinct OHDs (109 with AD inheritance, 102 with AR inheritance, and 30 with XL inheritance). Three diseases were particularly prevalent in this population and have not been documented in similar studies: congenital myasthenia type 12, a rare form of congenital adrenal cortex dysfunction (3-beta-hydroxysteroid dehydrogenase deficiency), and brachydactyly E - amelogenesis - mental retardation - nanism syndrome. Thus, the population of the RNO-A exhibits a unique spectrum of OHDs caused by rare mutations, some of which are infrequent in other populations of the world and the Russian Federation. The significantly higher prevalence of these disorders in rural populations is noteworthy, underscoring the need for tailored, region-specific programs aimed at preventing childhood disability and/or mortality.

В работе обобщены результаты описания популяционно-генетических характеристик населения Северной Осетии – Алании, полученные в ходе комплексного генетико-эпидемиологического обследования населения Республики. Корреляционный анализ показал хорошее соответствие полученных параметров. The article summarizes the results of the description of the population and genetic characteristics of the population of North Ossetia - Alania, obtained during a comprehensive genetic and epidemiological survey of the population of the Republic. The correlation analysis showed a good correspondence of the obtained parameters.

Буллезный эпидермолиз (БЭ) относится к группе редко встречающихся заболеваний кожи, которые характеризуются образованием пузырей, эрозий на кожных покровах и слизистых оболочках. Данная патология относится к орфанным заболеваниям, является генетически обусловленной, с разным типом наследования. Базальный слой эпидермиса, зона базальной мембраны и внеклеточный матрикс занимают центральное место в патофизиологии заболевания, а генетические нарушения изменяют структуру или функцию их белков. Мутации затрагивают 20 генов, что объясняет генетическую и клиническую гетерогенность БЭ с формированием четырех основных типов БЭ, включающих более 30 клинических подтипов. Важным диагностическим критерием при буллезном эпидермолизе является ДНК-диагностика. Количество новорожденных детей в Республике Северная Осетия – Алания с 2010 по 2022 г. составило 124 730 человек, при этом диагноз БЭ был подтвержден на молекулярногенетическом уровне в 2 случаях. Таким образом, за исследуемый период распространенность заболевания составила 1 на 62 365, или 1,6 на 100 000 новорожденных, или 16 случаев на 1 млн, что свидетельствует о достаточно высокой распространенности данной патологии в регионе. Epidermolysis bullosa (EB) belongs to the group of rare skin diseases that are characterized by the formation of blisters and erosions on the skin and mucous membranes. This pathology is an orphan disease and is genetically determined, with different types of inheritance. The basal layer of the epidermis, the basement membrane zone, and the extracellular matrix are central to the pathophysiology of the disease, and genetic changes determine the structure or function of their proteins. Mutations affect 20 genes, and this explains the genetic and clinical heterogeneity of EB with the formation of four main types of EB, including more than 30 clinical subtypes. An important diagnostic criterion for epidermolysis bullosa is DNA diagnostic. The number of newborn children in North Ossetia-Alania from 2010 to 2022 was 124,730 people, while the diagnosis of EB was confirmed at the molecular genetic level in 2 cases. Thus, during the study period, the prevalence of the disease was 1 per 62,365 or 1.6 per 100,000 newborns or 16 cases per 1 million, which indicates a fairly high prevalence of this pathology in the region.

Background: This study presents the findings of a newborn screening (NBS) pilot project for 5q-spinal muscular atrophy (5q-SMA) in multiple regions across Russia for during the year 2022. The aim was to assess the feasibility and reproducibility of NBS for SMA5q in diverse populations and estimate the real prevalence of 5q-SMA in Russia as well as the distribution of patients with different number of SMN2 copies. Methods: The pilot project of NBS here was based on data, involving the analysis of 202,908 newborns. SMA screening assay was performed using a commercially available real-time polymerase chain reaction kit, the Eonis SCID-SMA. Results: In one year, 202,908 newborns were screened, identifying 26 infants with homozygous deletion of SMN1 exon 7, yielding an estimated 5q-SMA incidence of 1:7804 newborns. It was found that 38.46% had two SMN2 copies, 42.31% had three copies, 15.38% had four copies, and 3.85% had five copies of SMN2. Immediate treatment was proposed for patients with two or three SMN2 copies. Infants with four or more SMN2 copies warranted further investigation on management and treatment. Short-term monitoring after gene therapy showed motor function improvements. Delays in treatment initiation were observed, including the testing for adeno-associated virus 9 antibodies and nonmedical factors. Conclusions: The study emphasizes the need for a standardized algorithm for early diagnosis and management through NBS to benefit affected families. Overall, the NBS program for 5q-SMA in Russia demonstrated the potential to improve outcomes and transform SMA from a devastating disease to a chronic condition with evolving medical requirements. (c) 2024 Elsevier Inc. All rights reserved.

В статье описаны результаты эпидемиологического мониторинга врожденных пороков развития у детей в Республике Северная Осетия-Алания с 2011 по 2022 годы. Наибольший вклад в структуру изолированных врожденных пороков вносят пороки сердечно-сосудистой и костно-мышечной систем и другие аномалии развития. Самыми частыми пороками развития по данным EUROCAT, в целом по РФ и по нашим региональным данным являются гипоспадия, синдром Дауна, расщелина губы и/ или неба. Более низкая частота в регионе отмечена для спинномозговой грыжи, дефектов брюшной стенки, атрезии пищевода, редукционных пороков конечностей и изолированных расщелин неба. Более высокая частота в республике по сравнению с данными EUROCAT и данными по РФ наблюдалась для транспозиции крупных сосудов. Частота врожденных пороков развития обязательного учета за этот период времени составила 15,11 на 1000 новорожденных или 1:66 новорожденных с вариацией по годам. В РСО-Алания наблюдается более высокая частота ВПР, чем в среднем по стране. The results of epidemiological monitoring of congenital malformations in children in the Republic of North Ossetia-Alania from 2011 to 2022 are described. The main contribution to the structure of isolated congenital defects is made by defects of the cardiovascular system, musculoskeletal system and other developmental anomalies. The most common malformations, both according to EUROCAT data for the Russian Federation as a whole, and according to our regional data, are hypospadias, Down syndrome, and cleft lip/palate. Lower incidence in the region is typical for spinal bifida, abdominal wall defects, esophageal atresia, reduction malformations of the limbs, and cleft palate. A higher frequency in the republic compared to EUROCAT data and data for the Russian Federation is typical for transposition of large vessels. The frequency of congenital malformations of mandatory registration during this period of time was 15.11 per 1000 newborns or 1:66 newborns with variation over the years. In North Ossetia-Alania there is a higher incidence of congenital malformations than the national average

This study is aimed at investigating the clinical and genetic characteristics of 244 unrelated probands diagnosed with multiple osteochondromas (MO). The diagnosis of MO typically involves identifying multiple benign bone tumors known as osteochondromas (OCs) through imaging studies and physical examinations. However, cases with both OCs and enchondromas (ECs) may indicate the more rare condition metachondromatosis (MC), which is assumed to be distinct disease. Previous cohort studies of MO found heterozygous loss-of-function (LoF) variants only in the EXT1 or EXT2 genes, with DNA diagnostic yield ranging from 78 to 95%. The PTPN11 gene, which is causative for MC, was not previously investigated as a gene candidate for MO. In this study, we detected a total of 177 unique single nucleotide and copy number variants in three genes across 220 probands, consisting of 80 previously reported and 97 novel variants. Specifically, we identified five cases with OCs and no ECs as well as four cases with MC carrying LoF variants in the PTPN11 gene and two additional cases with ECs harboring variants in the EXT1/2 genes. These findings suggest a potential overlap between the MO and MC both phenotypically and genetically. These findings highlight the importance of expanding genetic testing beyond the EXT1 and EXT2 genes in MO cases, as other genes such as PTPN11 may also be causative. This can improve the accuracy of diagnosis and treatment for individuals with MO and MC. It is essential to determine whether MO and MC represent distinct diseases or if they encompass a broader clinical spectrum.