vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/vjgb-26-78vavilov-5231Research ArticleМЕДИЦИНСКАЯ ГЕНЕТИКАMEDICAL GENETICSАнализ спектра мутаций гена CFTR в ХМАО-ЮгреAnalysis of CFTR mutation spectrum in Yugra region (Russian Federation)ДонниковМ. Ю.DonnikovM. Yu.

Сургут, ХМАО-Югра

Surgut, KHMAO-Yugra

donnikov@gmail.comМорозкинаА. В.MorozkinaA. V.

Сургут, ХМАО-Югра

Surgut, KHMAO-Yugra

КоваленкоЛ. В.KovalenkoL. V.

Сургут, ХМАО-Югра

Surgut, KHMAO-Yugra

ДонниковаН. А.DonnikovaN. A.

Сургут, ХМАО-Югра

Surgut, KHMAO-Yugra

МещеряковВ. В.MescheryakovV. V.

Сургут, ХМАО-Югра

Surgut, KHMAO-Yugra

Медицинский институт Сургутского государственного университетаРоссияMedical Institute of Surgut State UniversityRussian FederationСургутский окружной клинический центр охраны материнства и детстваРоссияSurgut Regional Clinical Center for Protection of Maternity and ChildhoodRussian Federation202626082026305775781Copyright © Донников М.Ю., Морозкина А.В., Коваленко Л.В., Донникова Н.А., Мещеряков В.В., 20262026Донников М.Ю., Морозкина А.В., Коваленко Л.В., Донникова Н.А., Мещеряков В.В.Donnikov M.Y., Morozkina A.V., Kovalenko L.V., Donnikova N.A., Mescheryakov V.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/5231

Быстрый прогресс как в молекулярной диагностике, так и в таргетной терапии муковисцидоза (МВ) требует четкого понимания спектра мутаций в гене CFTR у населения, постоянно проживающего в крупном регионе любой страны. До сих пор нет опубликованных результатов ни одного комплексного генетического исследования пациентов с МВ из ХМАО-Югры (Западно-Сибирская часть России). Образцы геномной ДНК, полученные от группы из 54 пациентов с МВ, проживающих в Югре, были изучены с использованием трехэтапного молекулярно-генетического подхода: 1) ПДРФ-анализ для панели из 35 мажорных мутаций в гене CFTR; 2) NGS для полного секвенирования экзонов и экзон-интронных границ гена CFTR; 3) метод MLPA для поиска крупных генных перестроек. Поиск мажорных мутаций в гене CFTR в многоэтнической популяции Югры позволяет выявить лишь 76.6 % от всех мутаций, вызывающих МВ. Наиболее распространенными являются варианты F508del (rs113993960), 1677delTA (rs121908776), CFTRdele2,3, E92K (rs121908751), R1066C (rs78194216). Геномная ДНК 19 пациентов с МВ из исследуемой группы, у которых идентифицирован только один мутантный аллель, была проанализирована с помощью метода NGS с последующим исследованием методом MLPA. В результате выявлены 19 редких патогенных вариантов гена CFTR, включая пять новых вариантов, информация о которых отсутствует в базах данных мутаций гена CFTR. В целом трехступенчатый молекулярно-генетический подход, впервые примененный для когорты пациентов с МВ из ХМАО-Югры, позволил обнаружить 12 миссенсмутаций, 9 нонсенс-мутаций, 6 инсерций/делеций, 4 варианта сайта сплайсинга и 1 CNV. Три аллеля остались неидентифицированными. Расшифровка генетического груза пациентов с МВ, проживающих в ХМАО-Югре, позволяет обосновать рациональное назначение модуляторов белка CFTR с выраженным клиническим эффектом. Показана необходимость разработки регион-специфической панели тестирования на распространенные мутации в гене CFTR.

Rapid progress in both molecular diagnostics tools and targeted therapy for cystic fibrosis (CF) requires clear understanding of CFTR mutation spectrum in population constantly living in any large region of any country. There are still no published results of comprehensive genetic study of CF patients from the Yugra region (Western Siberian part of Russia). Three-step molecular genetic approach was used for gDNA samples derived from a group of 54 CF patients living in the Yugra region: (1) AFLP/RFLP was used for the panel of 35 major CFTR mutations; (2) NGS, for full sequencing of exons and exon-intron boundaries of CFTR gene; and (3) the MLPA technique, to search for large gene rearrangements. The search of major CFTR mutations in multiethnic Yugra population accounted for only 76.6 % of all CF-causing mutations. Most common were variants F508del (rs113993960), 1677delTA (rs121908776), CFTRdele2,3, E92K (rs121908751), R1066C (rs78194216). Genomic DNA samples from 19 CF patients from the tested group in which only one mutant allele was identified were analyzed by the NGS approach followed by MLPA. This allowed to reveal 19 rare pathogenic CFTR variants, including five new variants absent in CF mutation databases. Generally, three-tier molecular genetics approach applied for the first time for a Yugra-originated cohort of CF patients allowed to find 12 missense mutations, 9 nonsense ones, 6 in/dels, 4 splice-site variants, 1 CNV. Three alleles remained unidentified. Deciphering the genetic background for CF patients living in Yugra allowed to support rational administration of CFTR modulators with profound clinical effect. The need to develop a region-specific testing panel for common CFTR mutations is demonstrated.

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