vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJGB-23-63vavilov-3868Research ArticleБИОТЕХНОЛОГИЯ В ПОСТГЕНОМНУЮ ЭРУMEDICAL GENETICSПоиск новых генов, ассоциированных с фенотипом семейной гиперхолестеринемии, методами полногеномного секвенирования и машинного обученияSearching for new genes associated with the familial hypercholesterolemia phenotype using whole-genome sequencing and machine learninghttps://orcid.org/0000-0002-0403-545XИванощукД. Е.IvanoshchukD. E.

Новосибирск

Novosibirsk

dinara2084@mail.ruhttps://orcid.org/0000-0002-7048-6419КолкерА. Б.KolkerA. B.

Новосибирск

Novosibirsk

https://orcid.org/0000-0002-6584-2060ТимощенкоО. В.TimoshchenkoO. V.

Новосибирск

Novosibirsk

https://orcid.org/0000-0003-3999-8501СемаевС. Е.SemaevS. E.

Новосибирск

Novosibirsk

https://orcid.org/0000-0001-6108-1025ШахтшнейдерЕ. В.ShakhtshneiderE. V.

Новосибирск

Novosibirsk

Научно-исследовательский институт терапии и профилактической медицины – филиал Федерального исследовательского центра Институт цитологии и генетики Сибирского отделения Российской академии наук; Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of Sciences; Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian FederationНовосибирский государственный технический университетРоссияNovosibirsk State Technical UniversityRussian FederationНаучно-исследовательский институт терапии и профилактической медицины – филиал Федерального исследовательского центра Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Internal and Preventive Medicine – Branch of the Institute of Cytology and Genetics of the Siberian Branch of the Russian Academy of SciencesRussian Federation202309092023275522529Copyright © Иванощук Д.Е., Колкер А.Б., Тимощенко О.В., Семаев С.Е., Шахтшнейдер Е.В., 20232023Иванощук Д.Е., Колкер А.Б., Тимощенко О.В., Семаев С.Е., Шахтшнейдер Е.В.Ivanoshchuk D.E., Kolker A.B., Timoshchenko O.V., Semaev S.E., Shakhtshneider E.V.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/3868

Одним из наиболее распространенных врожденных метаболических нарушений является семейная гиперхолестеринемия. Это заболевание приводит к раннему развитию сердечно-сосудистых заболеваний атеросклеротического генеза. Семейная гиперхолестеринемия относится к моногенным заболеваниям с преимущественно аутосомно-доминантным типом наследования. Редкие патогенные варианты в гене LDLR определяются в 75–85 % случаев у пациентов с выявленной молекулярно-генетической причиной заболевания, варианты в других генах встречаются с частотой менее 5 % (APOB, PCSK9, LDLRAP1, ABCG5, ABCG8 и др.). Отрицательный результат генетического скрининга патогенных вариантов генов рецептора липопротеинов низкой плотности и его лигандов не исключает диагноз «семейная гиперхолестеринемия». В 20–40 % случаев при молекулярно-генетическом исследовании не удается определить изменения в вышеназванных генах. Цель настоящей работы – поиск новых генов, ассоциированных с фенотипом семейной гиперхолестеринемии, с использованием современных высокотехнологичных методов секвенирования и машинного обучения. На основании выборки пациентов с семейной гиперхолестеринемией, сформированной по критериям Dutch Lipid Clinic Network и включающей случаи заболевания, подтвержденные молекулярно-генетическим анализом, построены решающие деревья, которые позволили выделить из выборки случаи, требующие дополнительного молекулярно-генетического анализа. Определены пять пробандов с наиболее тяжелым течением семейной гиперхолестеринемии без патогенных вариантов в изученных генах для проведения полногеномного секвенирования на платформе HiSeq 1500 (Illumina). При выполнении полногеномного секвенирования у трех из пяти обследованных пациентов найдены редкие варианты: гетерозиготный вариант (rs760657350), локализованный в акцепторном сайте сплайсинга гена PLD1: c.2430-1G>A, ранее не описанная однонуклеотидная делеция гена SIDT1: c.2426del (p.Leu809CysfsTer2), новый миссенс-вариант c.10313C>G (p.Pro3438Arg) гена LRP1B и вариант однонуклеотидной делеции rs753876598: c.165del (p.Ser56AlafsTer11) гена CETP. Все варианты впервые описаны у пробандов с клиническим диагнозом «семейная гиперхолестеринемия». Идентифицированы варианты, которые потенциально могут влиять на формирование фенотипа семейной гиперхолестеринемии.

One of the most common congenital metabolic disorders is familial hypercholesterolemia. Familial hyper-cholesterolemia is a condition caused by a type of genetic defect leading to a decreased rate of removal of low-density lipoproteins from the bloodstream and a pronounced increase in the blood level of total cholesterol. This disease leads to the early development of cardiovascular diseases of atherosclerotic etiology. Familial hypercholesterolemia is a monogenic disease that is predominantly autosomal dominant. Rare pathogenic variants in the LDLR gene are present in 75–85 % of cases with an identified molecular genetic cause of the disease, and variants in other genes (APOB, PCSK9, LDLRAP1, ABCG5, ABCG8, and others) occur at a frequency of < 5 % in this group of patients. A negative result of genetic screening for pathogenic variants in genes of the low-density lipoprotein receptor and its ligands does not rule out a diagnosis of familial hypercholesterolemia. In 20–40 % of cases, molecular genetic testing fails to detect changes in the above genes. The aim of this work was to search for new genes associated with the familial hypercholesterolemia phenotype by modern high-tech methods of sequencing and machine learning. On the basis of a group of patients with familial hypercholesterolemia (enrolled according to the Dutch Lipid Clinic Network Criteria and including cases confirmed by molecular genetic analysis), decision trees were constructed, which made it possible to identify cases in the study population that require additional molecular genetic analysis. Five probands were identified as having the severest familial hypercholesterolemia without pathogenic variants in the studied genes and were analyzed by whole-genome sequencing on the HiSeq 1500 platform (Illumina). The whole-genome sequencing revealed rare variants in three out of five analyzed patients: a heterozygous variant (rs760657350) located in a splicing acceptor site in the PLD1 gene (c.2430-1G>A), a previously undescribed single-nucleotide deletion in the SIDT1 gene [c.2426del (p.Leu809CysfsTer2)], new missense variant c.10313C>G (p.Pro3438Arg) in the LRP1B gene, and single-nucleotide deletion variant rs753876598 [c.165del (p.Ser56AlafsTer11)] in the CETP gene. All these variants were found for the first time in patients with a clinical diagnosis of familial hypercholesterolemia. Variants were identified that may influence the formation of the familial hypercholesterolemia phenotype.

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