Russian Journal of Genetics

Генетика

0016-67583034-5103

The Russian Academy of Sciences

666833

10.31857/S0016675823070032

QJIMJH

ГЕНЕТИКА ЧЕЛОВЕКА

Genetic Variation in Titin in Patients with Hypertrophic and Non-Compact Cardiomyopathy

Вариабельность гена титина у пациентов с гипертрофической и некомпактной кардиомиопатией

Chakova

N. N.

Чакова

Н. Н.

n.chakova@igc.by

Shulinski

R. S.

Шулинский

Р. С.

n.chakova@igc.by

Komissarova

S. M.

Комиссарова

С. М.

n.chakova@igc.by

Dolmatovich

T. V.

Долматович

Т. В.

n.chakova@igc.by

Niyazova

S. S.

Ниязова

С. С.

n.chakova@igc.by

Mazur

O. Ch.

Мазур

О. Ч.

n.chakova@igc.by

Ivanova

A. S.

Иванова

А. С.

n.chakova@igc.by

Liaudanski

A. D.

Левданский

О. Д.

n.chakova@igc.by

Institute of Genetics and Cytology of the National Academy of Sciences of BelarusИнститут генетики и цитологии Национальной академии наук Беларуси

Republican Scientific and Practical Centre “Cardiology”Республиканский научно-практический центр “Кардиология”

01072023

59781382726022025

2023

Н.Н. Чакова, Р.С. Шулинский, С.М. Комиссарова, Т.В. Долматович, С.С. Ниязова, О.Ч. Мазур, А.С. Иванова, О.Д. Левданский

https://transsyst.ru/0016-6758/article/view/666833

Using NGS, the coding sequence of the TTN gene was sequenced in patients with left ventricular non-compaction cardiomyopathy (LVNC, 44 individuals) and hypertrophic cardiomyopathy (HCM, 74 individuals), as well as in the control (194 individuals), and 9 nucleotide variants leading to truncated titin (TTNtv) and 372 missense variants were identified. A comparative analysis of the genetic variability of titin between the groups of patients with LVNC and HCM and the control sample was carried out in terms of the type of mutations and their localization in the exons of genes, as well as in the sarcomeric and functional domains of the protein. The role of TTNtv in the development of LVNC was confirmed, and the significance of additional variants in the same gene or in other genes associated with various cardiomyopathies for the phenotypic implementation of TTNtv was demonstrated. 75% of patients with TTNtv had a dilated LVNC phenotype. Missense substitutions in the TTN gene were found both among the patients with LVNC and HCM, and in people in the control sample, which indirectly confirms that most missense variants in this gene are benign. The paper identifies and lists highly mutable and conserved exons of the TTN gene and also presents a list of missense mutations with possible clinical significance in relation to the structural pathology of the myocardium, including new variants. It was shown that the majority of pathogenic and potentially significant mutations were located in the A-zone of the sarcomere. In all the groups, about 30–50% of new variants were identified. Probably, many of them are neutral and are of exclusively population interest.

С использованием NGS секвенирована кодирующая последовательность гена TTN у пациентов с некомпактным миокардом левого желудочка (НКМ, 44 человека) и гипертрофической кардиомиопатией (ГКМП, 74 человека), а также в контрольной группе (194 человека) и выявлено девять нуклеотидных вариантов, приводящих к укороченному титину (TTNtv), и 372 миссенс-варианта. Проведен сравнительный анализ генетической изменчивости титина между группами пациентов с НКМ и ГКМП и контрольной выборкой по типу мутаций и их локализации в экзонах гена, а также в саркомерных и функциональных доменах белка. Подтверждена роль TTNtv в развитии НКМ, а также показана значимость дополнительных вариантов в этом же гене или в других генах, ассоциированных с различными кардиомиопатиями, для фенотипической реализации TTNtv. У 75% пациентов с TTNtv наблюдался дилатационный фенотип НКМ. Миссенс-замены в гене TTN обнаружены как среди пациентов с НКМ и ГКМП, так и у людей в контрольной выборке, что косвенно подтверждает доброкачественность большинства миссенс-вариантов в этом гене. В работе определены и перечислены экзоны гена TTN с нуклеотидными заменами и без них, а также представлен перечень миссенс-вариантов с возможной клинической значимостью в отношении структурной патологии миокарда, включая новые. Показано, что большинство патогенных и потенциально значимых вариантов находились в А-зоне саркомера. Во всех группах выявлено порядка 30–50% новых, ранее не описанных вариантов. Вероятно, многие из них являются нейтральными и представляют исключительно популяционный интерес.

TTN genetitin-truncating variants (TTNtv)missense-mutationspathogenic significance of mutationshypertrophic cardiomyopathyleft ventricular non-compaction cardiomyopathy.

ген TTNукорачивающие титин мутациимиссенс-мутациипатогенная значимость нуклеотидных вариантовгипертрофическая кардиомиопатиянекомпактная кардиомиопатия левого желудочка.

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