vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-52vavilov-5117Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSДиагностическая эффективность полноэкзомного секвенирования в поиске генетических причин наследственных заболеваний в ХМАО-Югре (Западная Сибирь, Россия)Diagnostic efficiency of whole exome sequencing in the search for genetic causes of hereditary diseases in Yugra (West Siberia, Russia)ДонниковМ. Ю.DonnikovM. Yu.

Сургут, ХМАО-Югра

KHMAO-Yugra, Surgut

donnikov@gmail.comСучкоП. А.SuchkoP. A.

Санкт-Петербург

St. Petersburg

МорозкинаА. В.MorozkinaA. V.

Сургут, ХМАО-Югра

KHMAO-Yugra, Surgut

КолбасинЛ. Н.KolbasinL. N.

Сургут, ХМАО-Югра

KHMAO-Yugra, Surgut

ПоповаЕ. А.PopovaE. A.

Сургут, ХМАО-Югра

KHMAO-Yugra, Surgut

ПапановС. И.PapanovS. I.

Сургут, ХМАО-Югра

KHMAO-Yugra, Surgut

КошеваяЮ. С.KoshevayaYu. S.

Санкт-Петербург

St. Petersburg

ДаниловЛ. Г.DanilovL. G.

Санкт-Петербург

St. Petersburg

ЭйсмонтЮ. А.EismontYu. A.

Санкт-Петербург

St. Petersburg

ГлотовО. С.GlotovO. S.

Санкт-Петербург

St. Petersburg

КоваленкоЛ. В.KovalenkoL. V.

Сургут, ХМАО-Югра

KHMAO-Yugra, Surgut

Медицинский институт, Сургутский государственный университетРоссияMedical Institute of Surgut State UniversityRussian FederationНаучно-исследовательский институт акушерства, гинекологии и репродуктологии им. Д.О. Отта; Санкт-Петербургский государственный университетРоссияResearch Institute of Obstetrics, Gynecology, and Reproductology named after D.O. Ott; Saint Petersburg State UniversityRussian FederationМедицинский институт, Сургутский государственный университет; Сургутский окружной клинический центр охраны материнства и детстваРоссияMedical Institute of Surgut State University; KHMAO-Yugra Surgut Regional Clinical Center for Maternity and Childhood Protection, Medical Genetic Counseling ServiceRussian FederationДиагностический центр (медико-генетический)РоссияSaint-Petersburg State Medical Diagnostic Center (Genetic Medical Center)Russian FederationСанкт-Петербургский государственный университетРоссияSaint Petersburg State UniversityRussian FederationФедеральный научно-клинический центр инфекционных болезней Федерального медико-биологического агентстваРоссияFederal Scientific and Clinical Center of Infectious Diseases of the Federal Medical and Biological AgencyRussian FederationНаучно-исследовательский институт акушерства, гинекологии и репродуктологии им. Д.О. Отта; Федеральный научно-клинический центр инфекционных болезней Федерального медико-биологического агентстваРоссияResearch Institute of Obstetrics, Gynecology, and Reproductology named after D.O. Ott; Federal Scientific and Clinical Center of Infectious Diseases of the Federal Medical and Biological AgencyRussian Federation202626052026303482489Copyright © Донников М.Ю., Сучко П.А., Морозкина А.В., Колбасин Л.Н., Попова Е.А., Папанов С.И., Кошевая Ю.С., Данилов Л.Г., Эйсмонт Ю.А., Глотов О.С., Коваленко Л.В., 20262026Донников М.Ю., Сучко П.А., Морозкина А.В., Колбасин Л.Н., Попова Е.А., Папанов С.И., Кошевая Ю.С., Данилов Л.Г., Эйсмонт Ю.А., Глотов О.С., Коваленко Л.В.Donnikov M.Y., Suchko P.A., Morozkina A.V., Kolbasin L.N., Popova E.A., Papanov S.I., Koshevaya Y.S., Danilov L.G., Eismont Y.A., Glotov O.S., Kovalenko L.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5117

Полноэкзомное секвенирование произвело революцию в диагностике наследственных заболеваний, однако его эффективность варьирует в разных популяциях. Данные о генетической архитектуре редких наследственных заболеваний во многих регионах России, включая этнически разнообразный Ханты-Мансийский автономный округ – Югру, ограниченны. Настоящее исследование направлено на оценку диагностической ценности полноэкзомного секвенирования для выявления генетических вариантов, ассоциированных с наследственными заболеваниями в этой этнически неоднородной популяции. В исследование включили 286 пробандов с предполагаемыми наследственными заболеваниями, наблюдаемых генетиками региона в период с 2021 по 2024 г. Полноэкзомное секвенирование было выполнено на платформе DNBSEQ-G50 (MGI, Китай). Биоинформатический анализ включал выявление и аннотацию вариантов с использованием популяционных баз данных и инструментов прогнозирования патогенности. Найденные варианты были распределены по категориям в соответствии с рекомендациями ACMG/Российского общества медицинских генетиков и коррелировали с клиническими фенотипами. Молекулярно-генетические диагнозы были классифицированы как полные, частичные, потенциальные (на основании вариантов неизвестной значимости) или отсутствующие. Обследованная когорта преимущественно состояла из детей, наиболее частыми клиническими показаниями были неврологические, дисморфические и метаболические нарушения. Окончательный молекулярно-генетический диагноз был установлен у 24.8 % пациентов. С учетом потенциальных заключений общая значимость исследования увеличилась до 48.6 %. Диагностическая эффективность значительно варьировала в зависимости от категории заболеваний: от 58.3 % для заболеваний почек до 0 % для нарушений нейрогенеза. Проанализировано в общей сложности 420 уникальных вариантов генов, при этом миссенс-варианты были самыми встречающимися среди клинически значимых результатов. Наиболее часто выявлялись гены ATP7B, GJB2, ABCA4, GALT. Результаты исследования показали, что полноэкзомное секвенирование – эффективный молекулярный тест первой линии для широкого спектра предполагаемых наследственных заболеваний у жителей Югры с диагностической ценностью, сопоставимой с аналогичными исследованиями за рубежом. Полученные данные подтверждают результативность полноэкзомного секвенирования в гетерогенной популяции и подчеркивают потенциал повышения диагностической ценности за счет формата «трио» и периодического повторного анализа данных. 

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.

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The authors declare that there are no conflicts of interest present.