Russian Journal of GeneticsRussian Journal of GeneticsГенетика0016-67583034-5103The Russian Academy of Sciences66683810.31857/S0016675823050107DRVHTNОБЗОРНЫЕ И ТЕОРЕТИЧЕСКИЕ СТАТЬИPathogenetics of CardiomyopathyПатогенетика кардиомиопатийKucherA. N.КучерА. Н.maria.nazarenko@medgenetics.ruSleptcovA. A.СлепцовА. А.maria.nazarenko@medgenetics.ruNazarenkoM. S.НазаренкоМ. С.maria.nazarenko@medgenetics.ruResearch Institute of Medical Genetics, Tomsk National Research Medical Center of the Russian Academy of SciencesНаучно-исследовательский институт медицинской генетики, Томский национальный исследовательский медицинский центр Российской академии наук0106202359661563226022025Copyright ©; 2023, А.Н. Кучер, А.А. Слепцов, М.С. НазаренкоCopyright ©; 2023, А.Н. Кучер, А.А. Слепцов, М.С. Назаренко2023А.Н. Кучер, А.А. Слепцов, М.С. НазаренкоА.Н. Кучер, А.А. Слепцов, М.С. Назаренкоhttps://transsyst.ru/0016-6758/article/view/666838

This review summarizes the current state of knowledge on the genetic factors of both primary or Mendelian cardiomyopathies (CMPs) and some of its secondary forms. Dozens of genes with pathogenic/probably pathogenic variants have been described for primary CMPs. In most cases, the spectrum of causal genetic variants is specific for different CMPs, but shared genes and variants are also discovered. On the one hand genetic causes of diseases have not been established for all cases of primary CMPs, but on the other hand pathogenic variants in Mendelian disease genes are also found for its secondary forms. The genetic component in the development of both primary and secondary CMPs was also established during genome-wide association studies (GWAS). Single nucleotide polymorphisms (SNPs) associated with both primary and secondary CMPs are in most cases specific for different types of disease and make a small contribution to an individual’s overall risk. The link between some SNPs and electro- or echocardiogram features of the normal heart has been reported in the population. Most of the CMPs-associated SNPs are localized in non-coding regions of the genome, but they have a regulatory potential, acting in the heart as loci that affect the level of expression (eQTL), splicing (sQTL) or epigenetic modifications. It is noteworthy that the effects of the eQTL and sQTL genotypes in some cases are not equivalent for different anatomical regions of the heart. The phenotype and clinical presentation of CMPs in general can be determined by a wide range of rare pathogenic/probably pathogenic variants with a strong effect and common polymorphisms with a small effect and modified by epigenetic factors.

Анализируется значимость генетических факторов в развитии как первичных (или менделевских) кардиомиопатий (КМП), так и некоторых вторичных (приобретенных) форм КМП. Для первичных КМП описаны десятки генов с патогенными/вероятно патогенными вариантами. В большинстве случаев спектр причинных генетических вариантов для разных КМП специфичен, но регистрируются также общие гены и варианты. При этом, с одной стороны, не для всех случаев первичных КМП установлены генетические причины заболеваний, а с другой, патогенные варианты в генах менделевских КМП регистрируются и при вторичных КМП. Генетический компонент в развитии и первичных и вторичных КМП установлен также при проведении широкогеномных ассоциативных исследований (GWAS). Однонуклеотидные варианты (SNPs), ассоциированные и с первичными, и со вторичными КМП, в большинстве случаев специфичны для разных КМП и вносят небольшой вклад в риск развития патологий. Для некоторых SNPs установлены ассоциации с ЭКГ- и Эхо-кардиографическими параметрами морфологически неизмененного сердца у человека. Большинство из SNPs, ассоциированных с КМП по данным GWAS, локализованы в некодирующих участках генома, но обладают регуляторным потенциалом, выступая в ткани сердца в качестве локусов, влияющих на уровень экспрессии (eQTL), сплайсинг (sQTL) или эпигенетические модификации. Примечательно, что эффекты генотипов eQTL и sQTL в ряде случаев неравнозначны для различных анатомических отделов сердца. В целом фенотип и клиническая картина КМП могут определяться широким спектром редких патогенных/вероятно патогенных вариантов с сильным эффектом и частых высокополиморфных вариантов с небольшим эффектом и модифицироваться эпигенетическими факторами.

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