medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2024.03.38-48medgen-2455Research ArticleОРИГИНАЛЬНЫЕ ИССЛЕДОВАНИЯORIGINAL RESEARCHХарактеристика мутаций в гене FBN1 и оценка их патогенного статуса у пациентов с синдромом МарфанаCharacterization of mutations in the FBN1 gene and assessment of their pathogenic status in patients with Marfan syndromeЧаковаН. Н.ChakovaN. N.

220072, г. Минск, ул. Академическая, д. 27

27, Akademicheskaya st., Minsk, 220072

n.chakova@igc.byРудойА. С.RudoyA. S.

220036, г. Минск, ул. Розы Люксембург, д.110Б

110Б Rosa Luxemburg st., Minsk, 220036

БуракЕ. А.BurakE. A.

220072, г. Минск, ул. Академическая, д. 27

27, Akademicheskaya st., Minsk, 220072

ВалюженичЯ. И.ValiuzhenichY. I.

220083, г. Минск, пр. Дзержинского, д. 83

83, Dzerzhinsky pr., Minsk, 220083

ДолматовичТ. В.DolmatovichT. V.

220072, г. Минск, ул. Академическая, д. 27

27, Akademicheskaya st., Minsk, 220072

НиязоваС. С.NiyazovaS. S.

220072, г. Минск, ул. Академическая, д. 27

27, Akademicheskaya st., Minsk, 220072

Институт генетики и цитологии НАН БеларусиБеларусьInstitute of Genetics and Cytology of the National Academy of Sciences of BelarusBelarusРеспубликанский научно-практический центр «Кардиология»БеларусьRepublican Scientific and Practical Centre of CardiologyBelarusБелорусский государственный медицинский университетБеларусьBelarusian State Medical UniversityBelarus2024130720242333848Copyright © Чакова Н.Н., Рудой А.С., Бурак Е.А., Валюженич Я.И., Долматович Т.В., Ниязова С.С., 20242024Чакова Н.Н., Рудой А.С., Бурак Е.А., Валюженич Я.И., Долматович Т.В., Ниязова С.С.Chakova N.N., Rudoy A.S., Burak E.A., Valiuzhenich Y.I., Dolmatovich T.V., Niyazova S.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/2455

Введение. Синдром Марфана (СМ) – одно из часто встречающихся заболеваний группы наследственных нарушений (дисплазий) соединительной ткани с распространенностью в популяции 2-3 случая на 10000 человек. Продолжительность жизни пациентов ограничивается поражениями сердечно-сосудистой системы – развитием острого расслоения грудной аорты. Диагноз устанавливается на основании Гентских критериев (2010), в которых основополагающим является обнаружение патогенной мутации в гене FBN1. В гене, расположенном на 15-й хромосоме и содержащем 66 экзонов (из них 65 кодирующих), на данный момент насчитывается более 3000 нуклеотидных вариантов. Базы данных патогенных мутаций постоянно пополняются сведениями о фенотипической картине уже описанных вариантов и найденных впервые.Цель: изучить спектр мутаций в гене FBN1 в белорусской выборке пациентов с СМ и оценить диагностическую значимость выявленных генетических вариантов.Методы. В исследование включен 21 неродственный пациент с СМ. Для верификации диагноза всем пациентам методом NGS проведено секвенирование кодирующей последовательности. Найденные замены подтверждались прямым секвенированием по Сэнгеру. Патогенность выявленных вариантов оценивалась согласно базам данных (ClinVar, HGMD) и критериям Американского сообщества медицинских генетиков (ACMG, 2015 г.).Результаты. У 10 из 21 (47,62 %) пациентов с клиническим диагнозом СМ выявлено 10 редких вариантов нуклеотидной последовательности гена FBN1, три (30%) из которых обнаружены впервые. Интерпретация патогенности в базах данных ClinVar и HGMD существенно различалась. Только один из 7 вариантов, описанных ранее, указан как патогенный в обеих базах (ClinVar, HGMD), 3 варианта имели неопределенную клиническую значимость (VUS, III класс) в базе ClinVar, при этом один из них (p.Cys1159Tyr) описан как диагностически значимый в HGMD (DM, IV–V класс). Вариант р.Asp2291Gly, представленный в ClinVar как VUS, и замена p.Cys2674Tyr, патогенная в ClinVar, отсутствовали в базе HGMD, а варианта p.Cys1956Arg, диагностически значимого в базе HGMD, не было в ClinVar. Описанный же ранее вариант p.Cys2617TrpfsTer65 на данный момент не зарегистрирован ни в одной из баз. Вариант p.Thr1020Ala был определен как VUS в обеих базах и характеризовался наиболее благоприятным течением заболевания. Три варианта обнаружены впервые и являются патогенными согласно критериям ACMG: c.3838G>C (p.Asp1280His), c.7694G>C (p.Cys2565Ser), c.7849T>C (p.Cys2617Arg). В работе приведено подробное описание фенотипического проявления новых мутаций. Большинство патогенных мутаций находились в экзонах 62 и 64.Заключение. Обнаружено 10 редких вариантов в гене FBN1, 9 из которых являлись патогенными согласно критериям ACMG (2015 г.). Для 4 (40%) вариантов данные в базах ClinVar и HGMD различались. Полученные данные указывают на необходимость уточнения интерпретации патогенности некоторых вариантов в гене FBN1. Использование данных двух баз позволило подтвердить патогенный статус для существенно большего количества вариантов. Три новых миссенс-варианта были патогенными по предикторам in silico и приводили к тяжелому течению СМ, что указывает на их диагностическую значимость.

Background. Marfan syndrome (MS) is one of the frequently occurring diseases of the connective tissue dysplasia group, with a population prevalence of 2-3 cases per 10000 people. The life expectancy of patients is limited by lesions of the cardiovascular system. Diagnosis is based on the Ghent criteria (2010), in which the detection of a pathogenic mutation in the FBN1 gene is important. The gene, located on the 15th chromosome and containing 66 exons (65 of them coding), currently has more than 3000 nucleotide variants. Databases of pathogenic mutations are constantly updated with information about phenotypic manifestation of variants already described and those found for the first time.Aim: to study the spectrum of mutations in the FBN1 gene in the Belarusian sample of patients with MS and to evaluate the diagnostic significance of the identified genetic variants.Methods. The study included 21 unrelated patients with CM. To verify the diagnosis, sequencing of coding sequence was performed in all patients by NGS method. The found substitutions were confirmed by direct Sanger sequencing. The pathogenicity of the identified variants was assessed according to databases (ClinVar, HGMD) and criteria of the American Community of Medical Geneticists (ACMG, 2015).Results. In 10 out of 21 (47.62 %) patients with clinical diagnosis of Marfan syndrome 10 rare variants of nucleotide sequence of FBN1 gene were detected, three (30 %) of which were detected for the first time. The interpretation of pathogenicity in the ClinVar and HGMD databases differed significantly. Only one of the 7 previously described variants is listed as a pathogenic mutation in both databases (ClinVar, HGMD), 3 variants had uncertain clinical significance (VUS, class III) in the ClinVar database, with one of them (p.Cys1159Tyr) described as diagnostically significant in HGMD (DM, class IV-V). The variant p.Asp2291Gly, represented as VUS in ClinVar, and the replacement p.Cys2674Tyr, pathogenic in ClinVar, were absent in the HGMD database, and the variant p.Cys1956Arg, diagnostically significant in the HGMD database, was not present in ClinVar. The previously described variant p.Cys2617TrpfsTer65 is currently not registered in either database. The variant p.Thr1020Ala was identified as VUS in both bases and was characterized by the most favorable course of the disease. Three variants were detected for the first time and are pathogenic according to ACMG criteria: c.3838G>C (p.Asp1280His), c.7694G>C (p.Cys2565Ser), c.7849T>C (p.Cys2617Arg). The paper provides a detailed description of the phenotypic manifestation of the new mutations. Most of the pathogenic mutations were located in exons 62 and 64.Conclusions. Ten rare variants in the FBN1 gene were detected, 9 of which were pathogenic according to the ACMG criteria (2015). For 4 (40%) variants the data in ClinVar and HGMD databases differed. The data obtained indicate the need to clarify the interpretation of pathogenicity of some variants in the FBN1 gene. The use of data from the two databases allowed us to confirm the pathogenic status for a significantly larger number of variants. Three new missense variants were pathogenic by in silico predictors and led to a severe course of MS, indicating their diagnostic significance.

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