Diagnostic efficiency of whole exome sequencing in the search for genetic causes of hereditary diseases in Yugra (West Siberia, Russia)

Whole-exome sequencing (WES) has revolutionized the diagnostics of hereditary diseases, yet its efficacy varies across populations. Data on the genetic architecture of rare hereditary disorders in many Russian regions, including the ethnically diverse Khanty-Mansi Autonomous Okrug (Yugra) are scarce. The aim of this study was to evaluate the diagnostic yield of WES for identifying genetic variants associated with hereditary disorders in this ethnically heterogeneous population. The study involved 286 probands with suspected hereditary disorders observed by regional geneticists in the years 2021-2024. WES was performed on the DNBSEQ-G50 platform (MGI, China). Bioinformatic analysis included variant calling and annotation using population databases and pathogenicity prediction tools. Identified variants were classified according to ACMG/Russian Medical Genetics Society guidelines and correlated with clinical phenotypes. Molecular genetic diagnoses were categorized as definitive, partial, potential (based on variants of unknown significance), or unknown. The examined cohort was predominantly pediatric, the most common clinical indications were neurological, dysmorphic, and metabolic disorders. Definitive molecular diagnoses were established in 24.8 % of patients. Inclusion of potential diagnoses increased the total yield to 48.6 %. Diagnostic efficacy varied significantly among disease categories ranging from 58.3 % for renal disorders to 0 % for neurodevelopmental disorders. A total of 420 unique variants were analyzed, and missense changes were the most frequent among clinically significant findings. The most commonly implicated genes were ATP7B, GJB2, ABCA4, and GALT. The study results indicate that WES is an effective first-tier molecular tool for a wide range of suspected hereditary diseases in the Yugra population, with a diagnostic yield comparable to similar studies abroad. The findings support the utility of WES in diverse populations and highlight the potential for increasing yield through trio-WES and periodic data reanalysis.