Evidence-Based Assessment of Genes in Dilated Cardiomyopathy

Abstract

Background: The cardiomyopathies, classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), each have a signature genetic theme. HCM and ARVC are largely understood as genetic diseases of sarcomere or desmosome proteins, respectively. In contrast, >250 genes spanning more than 10 gene ontologies have been implicated in DCM, representing a complex and diverse genetic architecture. To clarify this, a systematic curation of evidence to establish the relationship of genes with DCM was conducted. Methods: An international Panel with clinical and scientific expertise in DCM genetics evaluated evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework with modifications for DCM genetics to classify genes into categories based on the strength of currently available evidence. Representation of DCM genes on clinically available genetic testing panels was evaluated. Results: Fifty-one genes with human genetic evidence were curated. Twelve genes (23%) from eight gene ontologies were classified as having definitive ( BAG3, DES, FLNC, LMNA, MYH7, PLN, RBM20, SCN5A, TNNC1, TNNT2, TTN ) or strong ( DSP ) evidence. Seven genes (14%) ( ACTC1, ACTN2, JPH2, NEXN, TNNI3, TPM1, VCL ) including two additional ontologies were classified as moderate evidence; these genes are likely to emerge as strong or definitive with additional evidence. Of these 19 genes, six were similarly classified for HCM and three for ARVC. Of the remaining 32 genes (63%), 25 (49%) had limited evidence, 4 (8%) were disputed, 2 (4%) had no disease relationship, and 1 (2%) was supported by animal model data only. Of 16 evaluated clinical genetic testing panels, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In the curation of 51 genes, 19 had high evidence (12 definitive/strong; seven moderate). Notably, these 19 genes only explain a minority of cases, leaving the remainder of DCM genetic architecture incompletely addressed. Clinical genetic testing panels include most high evidence genes, however genes lacking robust evidence are also commonly included. We recommend that high evidence DCM genes be used for clinical practice and to exercise caution when interpreting variants in variable evidence DCM genes.

Phenotypic Expression and Outcomes in Individuals With Rare Genetic Variants of Hypertrophic Cardiomyopathy

“…Other variants that were consistent with known disease mechanisms and sufficiently rare, but not recorded in ClinVar and without other computationally available data to robustly classify as P/LP, were defined as indeterminate sarcomeric variants (SARC-IND) ( 25 , 26 ). Despite being curated for HCM, given that 5 of the 8 genes ( MYH7, ACTC1, TNNT2, TNNI3, and TPM1 ) that have definitive evidence for HCM have also been implicated in DCM ( 27 ), it is possible that some SARC-IND variants have the potential to cause DCM. The SARC-IND strata differs from those classically termed variants of unknown significance as it likely contains additional variants that would be reported as P/LP if subject to full manual curation, which is not feasible in >5,000 individuals (further subgroup investigations are presented in the Supplemental Appendix ).…”

Genetic risk factors for dilated cardiomyopathy

“…в 35-40% случаев аритмических фенотипов с нарушениями проводимости [10]. Изучение генотип-фенотипических корреляций и сравнение долгосрочных результатов в многоцентровых исследованиях больших когорт ДКМП показало, что мутации в определенных генах (например, варианты LMNA, DES, PLN и FLNC) связаны с высоким риском фатальных аритмий [5,10,11]. Некоторые исследования продемонстрировали хорошую эффективность оптимальной медикаментозной терапии у носителей TTNtv на ранней стадии болезни с обратимостью дилатационного ремоделирования миокарда [12,13].…”

“…В отличие от генетических причин гипертрофической кардиомиопатии (ГКМП) (в основном мутации в генах саркомерных белков) и аритмогенной кардиомиопатии (КМП) (преимущественные варианты в генах десмосом), генетическая природа ДКМП имеет значительное разнообразие. В настоящее время количество генов-кандидатов, которые, как предполагается, могут детерминировать развитие ДКМП, превысило сотню [5], однако причина столь выраженной генетической гетерогенности остается не до конца изученной. Следует отметить также значительное совпадение генов, участвующих в патогенезе ДКМП, других КМП и каналопатий, феномен смешанных и перекрывающихся фенотипов.…”

Cardiac magnetic resonance imaging characteristics for the differentiation of athlete’s heart from inherited cardiomyopathies

“…Over the past two decades, advances in noninvasive imaging and genetic sequencing have contributed importantly to our understanding of cardiomyopathies, and resulted in increased recognition of these potentially life-threatening but manageable conditions and their remarkable prevalence, conservatively estimated to be as high as 1/250 for DCM, 1/500 for HCM and 1/2000-1/5000 for ACM [5][6][7][8]. In addition, phenotypic mimics previously misdiagnosed as an inherited cardiomyopathy have been increasingly recognized in parallel to the implementation of more high-resolution imaging technologies.…”