evrazkarЕвразийский Кардиологический ЖурналEurasian heart journal2225-16852305-0748Евразийская ассоциация кардиологов10.38109/2225-1685-2023-2-26-37evrazkar-6386Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL PAPERSГенетический спектр семейной и спорадической дилатационной кардиомиопатии: аритмические фенотипы, ассоциированные с мутациями в гене ламина A/C (LMNA)Genetic spectrum of familial and sporadic dilated cardiomyopathy: arrhythmic phenotypes associated with mutations in the lamin A/C (LMNA) genehttps://orcid.org/0000-0002-2127-8525ВайханскаяТ. Г.VaikhanskayaT. G.

Вайханская Татьяна Геннадьевна, к.м.н., ведущий научный сотрудник лаборатории медицинских информационных технологий

ул. Р. Люксембург, д. 110 б, г. Минск 220036

Tatiyana G. Vaikhanskaya, Cand. of Sci. (Med.), Senior Research Scientist, Laboratory of Medical Information Technologies

st. R. Luxembourg, 110b, Minsk 220036

vaikh@mail.ruhttps://orcid.org/0000-0001-6359-4967СивицкаяЛ. Н.SivitskayaL. N.

Сивицкая Лариса Николаевна, к.б.н., ведущий научный сотрудник лаборатории нехромосомной наследственности; специалист по секвенированию диагностического отделения

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

ул. Пончова, д. 12, г. Варшава 02-971, Польша, lsivitskaya@yahoo.com

Larysa N. Sivitskaya, Cand. of Sci. (Biol.), Senior Research Scientist, Laboratory of Cytoplasmic Inheritance; Sequencing Specialist, Diagnostic Department

st. Akademicheskaya 27, Minsk 220072

st. Ponczowa 12, Warsaw 02-971, Poland, lsivitskaya@yahoo.com

cytoplasmic@mail.ruhttps://orcid.org/0000-0001-5727-3219КурушкоТ. В.KurushkaT. V.

Курушко Татьяна Валентиновна, врач отделения функциональной диагностики

ул. Р. Люксембург, д. 110 б, г. Минск 220036

Tatsyana V. Kurushka, Physician of the Department of Functional Diagnostics

st. R. Luxembourg, 110b, Minsk 220036

tatkuko@mail.ruhttps://orcid.org/0000-0002-3325-0917ЛевданскийО. Д.LiaudanskiA. D.

Левданский Олег Дмитриевич, к.б.н., старший научный сотрудник лаборатории нехромосомной наследственности

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

Aleg D. Liaudanski, Cand. of Sci. (Biol.), Senior Researcher, Laboratory of Cytoplasmic Inheritance

st. Akademicheskaya 27, Minsk 220072

o.liaudanski@igc.byhttps://orcid.org/0000-0002-3270-3080ДаниленкоН. Г.DanilenkoN. G.

Даниленко Нина Генусовна, к.б.н., ведущий научный сотрудник лаборатории нехромосомной наследственности

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

Nina G. Danilenko, Cand. of Sci. (Biol.), Senior Research Scientist, Laboratory of Cytoplasmic Inheritance

st. Akademicheskaya 27, Minsk 220072

cytoplasmic@mail.ruГУ Республиканский научно-практический центр «Кардиология»БеларусьState Institution Republican Scientific and Practical Center «Cardiology»BelarusГНУ Институт генетики и цитологии НАН БеларусиБеларусьState Research Institution «Institute of Genetics and Cytology of the National Academy of Sciences of Belarus»; Genomed Health CenterBelarusГНУ Институт генетики и цитологии НАН БеларусиБеларусьState Research Institution «Institute of Genetics and Cytology of the National Academy of Sciences of Belarus»Belarus202326052023022637Copyright © Вайханская Т.Г., Сивицкая Л.Н., Курушко Т.В., Левданский О.Д., Даниленко Н.Г., 20232023Вайханская Т.Г., Сивицкая Л.Н., Курушко Т.В., Левданский О.Д., Даниленко Н.Г.Vaikhanskaya T.G., Sivitskaya L.N., Kurushka T.V., Liaudanski A.D., Danilenko N.G.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.heartj.asia/jour/article/view/6386Цель исследования

Цель исследования. Изучение диагностической значимости каскад­ного семейного скрининга и спектра генетических вариантов у паци­ентов с семейной и спорадической дилатационной кардиомиопатией (ДКМП), оценка клинических исходов и сравнительный анализ 5-лет­ней бессобытийной выживаемости.

Материал и методы

Материал и методы. В исследование включили 156 неродственных пациентов с верифицированной ДКМП. Всем пациентам (возраст 46 [34;57] лет; 125 (80%) муж.; фракция выброса левого желудочка 31 [24; 38]%; период наблюдения - 77 [59;108] мес) проведен комплекс клинико-инструментальных исследований, каскадный семейный скри­нинг с генетическим исследованием (NGS+Sanger) и сегрегационный анализ.

Результаты

Результаты. У 73 (46,8%) пробандов выявлены критерии семейной ДКМП. В группе с семейной формой генетическая причина ДКМП определена в 47 (64,4%) случаях, у лиц со спорадической формой па­тогенные мутации выявлены у 19 (22,9%) пациентов. Доминирующи­ми мутациями были укорачивающие варианты в гене титина (10,9%) и варианты в гене ламина А/C (LMNA) - 8,33%. В результате оценки бессобытийной выживаемости (кривые Каплан-Мейера) у LMNA но­сителей выявлен худший 5-летний прогноз в достижении жизнеопас­ных желудочковых тахиаритмических событий (х2=39,9; р=0,0001) и комбинированных неблагоприятных исходов (х2=12,1; р=0,001). Более неблагоприятный прогноз и низкую кумулятивную выживаемость по­казали пробанды с семейной формой заболевания (log rang х2=38,5; р=0,0001) при сравнении с группой спорадической ДКМП.

Заключение

Заключение. Каскадный клинический семейный скрининг и генетиче­ское тестирование в когорте ДКМП позволили повысить уровень диа­гностики семейных форм ДКМП с 4,5% до 46,8%. Ассоциации LMNA мутаций с жизнеопасными тахиаритмиями определены на уровне про­гностической значимости, что подтверждает важную роль генетиче­ской стратификации аритмического риска.

Purpose

Purpose. To study the diagnostic value of cascade family screening and the spectrum of genetic variants in patients with familial and sporadic DCM, assess clinical outcomes and comparative analysis of 5-year event-free survival.

Materials and methods

Materials and methods. The study included 156 unrelated patients with verified DCM. All patients (aged 46 [34; 57] years; 125 (80%) male; LVEF 31 [24; 38]%; LV EDD 68 [61; 74] mm; follow-up period - 77 [59; 108] months) a complex of clinical and instrumental studies (ECG, ECHO, HM, MRI), cascade family screening with genetic testing (NGS+Sanger) and segregation analysis were performed.

Results

Results. Criteria for familial DCM were identified in 73 (46.8%) probands. The genetic cause of DCM was identified in 47 (64,4%) familial cases, while for sporadic form DCM pathogenic variants were detected in 19 (22,9%) patients. The dominant mutations were truncating variants in the titin gene (10,9%) and variants in the lamin A/C (LMNA) gene - 8,33%. As a result of the evaluation of cumulative event-free survival (Kaplan-Meier curves), LMNA carriers showed the poor 5-year prognosis for ventricular tachyarrhythmic events (x2=39.9; p=0,0001) and composite adverse outcomes (x2=12.1; p=0.001). Probands who had a familial DCM (log rang x2=38.5; p=0,0001) showed the worst prognosis and low cumulative survival when compared with patients of the sporadic DCM.

Conclusion

Conclusion. Cascade clinical family screening and genetic testing in the DCM cohort increased the level of diagnosis of familial DCM from 4.5% to 46.8%. Associations of LMNA mutations with life-threatening tachyarrhythmias are defined as prognostically significant, that confirms the important role of genetic stratification of arrhythmic risk.

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