Alagille syndrome (ALGS) is an inherited multisystem disorder with a broad phenotypic spectrum and no apparent genotype-phenotype correlation. This study aimed to present the clinical and genetic characteristics of 115 patients diagnosed with ALGS in the Russian Federation between 2010 and 2023. The most common pathogenic variants identified in the study cohort were c.2122_2125delCAGT p.(Gln708Valfs*34) and c.439+1G>A. Two previously undescribed JAG1 variants, c.247C>T p.(Gln83Ter) and c.1188del p.(Phe396Leufs*16), were assessed in silico as likely pathogenic. Functional analysis of four JAG1 variants (c.439+1G>A, c.1120+5G>A, c.886+3A>G, and c.1156G>A) and one NOTCH2 variant (c.1264+5G>A) using a minigene splicing assay classified them as pathogenic splice-site variants.

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.

Massovoe obsledovanie novorozhdennyh v Rossijskoj Federacii na 36 nasledstvennyh zabolevanij pozvolit snizit' detskuyu invalidnost' i smertnost' ot nasledstvennoj patologii i vyyavit' obshcherossijskie i regional'nye populyacionno-geneticheskie osobennosti skriniruemoj patologii. Cel'yu issledovaniya bylo ocenit' rezul'taty neonatal'nogo skrininga (NS), vklyuchaya rasshirennyj neonatal'nyj skrining (RNS) v Respublike Severnaya Osetiya-Alaniya (RSO-Alaniya) v period s 01.01.2023 po 31.12.2024, i izuchit' klinicheskie i populyacionno-geneticheskie osobennosti skriniruemyh zabolevanij v regione. Na I etape obsledovaniya u 14 994 novorozhdennyh provedeny biohimicheskie issledovaniya, tandemnaya mass-spektrometriya, DNK-diagnostika i opredelenie urovnya TREK/KREK. V 355 sluchayah (2,36%) vyyavleny pozitivnye znacheniya. Na II etape v 324 (91,2%) sluchayah provedena neobhodimaya laboratornaya i posleduyushchaya podtverzhdayushchaya DNK-diagnostika: povtornyj analiz v MS/MS i DNK-diagnostika (dlya nasledstvennyh boleznej obmena veshchestv), immunofenotipirovanie (dlya pervichnyh immunodeficitnyh sostoyanij). V hode dvuhletnego issledovaniya postavleno 37 diagnozov, chto sostavlyaet 0,25% ot vsekh detej, ohvachennyh skriningom na I etape, i odnoznachno svidetel'stvuet ob uspeshnosti i rezul'tativnosti dannoj programmy. Udalos' verificirovat' specificheskij spektr mutacij, harakternyh dlya fenilketonurii (FKU) i nedostatochnosti acil-KoA-degidrogenazy zhirnyh kislot so srednej dlinoj uglerodnoj cepi (MCADD). Opredelena chastota vstrechaemosti patologii, issleduemoj v ramkah neonatal'nogo skrininga. CHastota vsekh form FKU sostavila 1 : 1153 novorozhdennyh, a chastota MCADD — 1 : 789 obsledovannyh novorozhdennyh. Vse deti sostoyat na dispansernom uchete v mediko-geneticheskoj konsul'tacii RSO-Alaniya, poluchayut lechenie v sootvetstvii s klinicheskimi rekomendaciyami.

Duchenne muscular dystrophy (DMD) is typically described in boys with a pathogenic variant in the DMD. However, in certain cases, females may also exhibit symptoms of this X-linked disorder. In the present study, the cause of Duchenne muscular dystrophy in three girls was reciprocal translocations t(X;2), t(X;12), and t(X;16), with breakpoints located within the DMD gene sequence. All patients had global development delay, predominantly proximal muscle weakness, calf muscle hypertrophy, and elevated creatine kinase levels up to 100 times the normal range (16,000-26,694 U/L). All underwent cardiac ultrasound and electromyography, and two of the girls also had muscle MRI data. After receiving negative results of MLPA aimed at the detection of DMD deletions and duplications, as well as the limb-girdle muscular dystrophy gene panel sequencing, the patients were referred to whole genome sequencing, which allowed to detect a translocation involving the short arm of the X chromosome and with breakpoints in the DMD. Karyotyping confirmed reciprocal translocations in all patients, with de novo status established in all three cases. The results of this study contribute to the understanding of clinical polymorphism and genetic heterogeneity of the disease, highlighting the importance of a comprehensive approach to genetic diagnostics in atypical cases.

Since 2023, the Russian Federation (RF) has implemented an expanded newborn screening (NBS) program for 36 hereditary disorders, which now includes 5q spinal muscular atrophy (5q SMA). As a result of newborn screening for 5q SMA conducted in the RF during 2023-2024, 288 newborns with a homozygous deletion of exon 7 in the SMN1 gene were identified by molecular genetic methods. The overall observed incidence of 5q SMA was 1 in 8439 newborns, which does not significantly differ from the expected incidence of 1 in 7953 newborns, established by previous pilot screening projects (p > 0.05). A comparison of the genotypes of patients identified through selective and newborn screening showed statistically significant differences in the proportions of patients carrying two, three, and four or more copies of the SMN2 gene. These findings demonstrate that the NBS program is effective in detecting both individuals with more severe phenotypes, as expected, and those with milder forms of the disease.

Mass screening of newborns for 36 hereditary diseases in the Russian Federation will enable the reduction of childhood disability and mortality from hereditary disorders, as well as the identification of all-Russian and regional population-genetic features of the screened disorders. The study aimed to assess the results of newborn screening (NBS), including expanded newborn screening (ENBS), in the Republic of North Ossetia-Alania obtained between January 1, 2023, and December 31, 2024, as well as to study clinical and population-genetic characteristics of the diseases screened in the region. In phase I of assessment, biochemical testing, tandem mass spectrometry, and DNA diagnostics were performed, and the TREС/KREС levels were determined in 14,994 newborns. In 355 cases (2.36%), positive values were revealed. In phase II, the necessary laboratory and subsequent confirmatory DNA diagnostics were carried out in 324 cases (91.2%): repeated analysis by MS/MS and DNA diagnostics (for hereditary metabolic diseases), immunophenotyping (for primary immunodeficiency states). During the 2-year study, a total of 37 diagnoses were established, which accounted for 0.25% of all children screened in phase I and clearly indicated the program's success and effectiveness. We managed to verify the specific spectrum of mutations characteristic of phenylketonuria (PKU) and medium-chain fatty acid acyl-CoA dehydrogenase deficiency (MCADD). The frequency of the disorder assessed within the framework of newborn screening was determined. The frequency of all PKU forms was 1 : 1153 newborns, and the frequency of MCADD was 1 : 789 newborns surveyed. All children are listed as sick in the medical genetic consultation of the Republic of North Ossetia-Alania; they receive treatment in accordance with the clinical guidelines.

24-hydroxylase deficiency (or infantile hypercalcemia type 1) is an inherited disease associated with biallelic loss-of-function CYP24A1 mutations lead to impaired inactivation of vitamin D metabolites and characterised hypercalcemia, nephrocalcinosis and/or urolithiasis. We present 44 patients, the largest group (n=41) consisted of children. The main complaints at the time of examination was: weight loss, refusal to eat, delayed physical and/or psychomotor development, signs of urinary tract infection and/or nephrocalcinosis (in adults — urolithiasis). Hypercalcemia was detected in 88.6%, with Me 2.9 [2.65; 4.03] mmol/L. Me of the 25(OH)D3:24.25(OH)2D3 ratio was 340.65 [132.2; 630.75] (n=10). Hypercalciuria was detected in 59%, nephrocalcinosis or urolithiasis in 95% of cases. Frequent mutations in the CYP24A1 gene were p.Arg396Trp (66%) and p.Glu143del. (27%). Incidence of 24-hydroxylase deficiency in Russian population was 1:10900 estimated on the basis of these alleles of CYP24A1 , overall carrier frequency for these mutations in CYP24A1 was 1 in 53 people. In conclusion, we propose to conduct molecular testing for the presence of pathogenic variants p.Arg396Trp and p.Glu143del in CYP24A1 during neonatal screening, due to the high expected frequency of 24-hydroxylase deficiency and heterozygous carriage of pathogenic variants of CYP24A1 in Russia.

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).

During the expanded neonatal screening program conducted in 2023, we analyzed samples obtained from 1,227,130 out of 1,256,187 newborns in the Russian Federation in order to detect 5q spinal muscular atrophy (5q SMA). Within the 253-sample risk group formed based on the results of the first screening stage, 5 samples showed a discrepancy between the examination results obtained via various screening methods and quantitative MLPA (used as reference). The discrepancy between the results was caused by the presence of either a c.835-18C>T intronic variant or a c.842G>C p.(Arg281Thr) missense variant in the SMN1 gene, both of which are located in the region complementary to the sequences of annealing probes for ligation and real-time PCR. Three newborns had the c.835-18C>T variant in a compound heterozygous state with a deletion of exons 7–8 of the SMN1 gene, one newborn with two copies of the SMN1 gene had the same variant in a heterozygous state, and one newborn had both variants—c.835-18C>T and c.842G>C p.(Arg281Thr)—in a compound heterozygous state. Additional examination was carried out for these variants, involving segregation analysis in families, carriage analysis in population cohorts, and RNA analysis. Based on the obtained results, according to the ACMG criteria, the c.835-18C>T intronic variant should be classified as likely benign, and the c.842G>C p.(Arg281Thr) missense substitution as a variant of uncertain clinical significance. All five probands are under dynamic monitoring. No 5q SMA symptoms were detected in these newborns neonatally or during a 1-year follow-up period.

Under the implementation of the “Advanced neonatal screening” Federal Program and the Ministry of Healthcare of Russia Order No. 274n “On approval of the Procedure for providing medical care to patients with congenital and/or hereditary diseases” that started jointly on Jan. 01, 2023 overall Russia, the examination of all newborns for the 29 nosologies of exchange disorders by tandem mass spectrometry as well as spinal muscular atrophy and primary immunodeficiencies by polymerase chain reaction had begun. Circa 1 million and 230 thousand newborns were examined in 85 Russia regions during 2023 with the level of births coverage exceeding 98%. As a result, a risk group that amounted to 1.86% of all examined was formed with confirming diagnostics performed for 8712 neonatal patients at risk, of which 676 have had their deceases confirmed including 379 hereditary metabolic diseases, 117 spinal muscular atrophies and 180 primary immunodeficiencies. Effective treatment and dispensary follow-up methods have been developed so far for all the screened nosologies. Thus, the introduction of the neonatal screening made it possible to initiate therapy for most of the identified patients at preclinical stages reducing the overall infant mortality and improving the quality of life for such patients and their caretakers.

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.