An Evidence-based Assessment of Genes in Dilated Cardiomyopathy

Abstract

Background: The cardiomyopathies are classically categorized as hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular (ARVC), and 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 was assembled to evaluate evidence supporting monogenic relationships of genes with idiopathic DCM. The Panel utilized the ClinGen semi-quantitative gene-disease clinical validity classification framework. 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 the 19 genes classified as definitive, strong or moderate, 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 commercially available genetic testing panels evaluated, most definitive genes were included, but panels also included numerous genes with minimal human evidence. Conclusions: In a systematic curation of published evidence for genes considered relevant for monogenic DCM, 12 were classified as definitive or strong and seven as moderate evidence spanning 10 gene ontologies. Notably, these 19 genes only explain a minority of DCM cases, leaving the remainder of DCM genetic architecture incompletely addressed. While clinical genetic testing panels include most high evidence genes, genes lacking robust evidence are also commonly included. Until the genetic architecture of DCM is more fully defined, care should be taken in the interpretation of variable evidence DCM genes in clinical practice.

A novel functional variant residing outside the SCN5A-encoded Nav1.5 voltage-sensing domain causes multifocal ectopic Purkinje-related premature contractions

“…Pathogenic variants in the SCN5A-encoded pore-forming α-subunit of the Nav1.5 voltage-gated cardiac sodium channel are associated with primary arrhythmia syndromes including type 3 long QT syndrome (LQT3; Nav1.5 gain-of-function), Brugada syndrome (BrS; Nav1.5 loss-offunction), early-onset atrial fibrillation (AF; Nav1.5 loss-and gain-of-function), primary cardiac conduction disease (PCCD; Nav1.5 loss-of-function), dilated cardiomyopathy (DCM; Nav1.5 lossand gain-of-function), and overlap syndromes, whereby the clinical hallmark(s) of more than one disorder is observed with the same patient and/or family. [1][2][3][4][5] Multifocal ectopic Purkinje-related premature contractions (MEPPC; Nav1.5 gain-offunction), a recently described SCN5A-mediated cardiac channelopathy, is characterized by frequent premature ventricular complexes (PVCs) originating from the fascicular-Purkinje system, atrial arrhythmias, a predilection for PVC-mediated dilated cardiomyopathy (DCM), and sudden cardiac death (SCD). 2,6 Thus far, only six MEPPC-causative SCN5A variants (p.Ala204Glu-SCN5A 3 , p.Gly213Asp-SCN5A 7 , p.Arg222Glu-SCN5A 6,8,9 , p.Arg225Pro-SCN5A 10 , p.Leu828Phe-SCN5A 11 , and p.Met1851Val-SCN5A 2 ) have been identified, most within the voltage-sensing domain (VSD) of Nav1.5.…”

Improved nanopore direct RNA sequencing of cardiac myocyte samples by selective mt-RNA depletion

“…As these RNAs usually are not polyadenylated, they can be classified as non-specific side product for the polyA-driven Nanopore direct RNA-seq approach and are removed during purification of the mt-clipped RNA. We further focused on genes from the top enriched GO terms, or implicated in DCM, analyzed in a recent study [19]. Here, we show that several genes are detected with a higher read coverage along the gene body.…”

“…Although more than 250 genes have been implicated in DCM [18], so far only for a subset of cases the genetic basis is understood. Recently, Jordan et al [19] performed an evidence-based assessment of genes that have been implicated in DCM. They classified a total number of 44 genes as "definitive", "strong", "moderate" or "limited" human genetic evidence with respect to their genetic contribution to DCM.…”

“…TPM1, encoding alpha-Tropomyosin is mutated in certain forms of DCM as well as hypertrophic cardiomyopathy (HCM) and mutations are supposed to alter actin filament dynamics [28]. TPM1 (located on chr15) was classified as definitive evidence in HCM [29] but only moderate evidence for DCM based on the not sufficient evidence supporting data [19]. TPM1 shows on average a 1.2 fold (±0.1) higher coverage along the gene body in mt-clipped compared to total samples (Fig.…”

“…More than 250 genes have been implicated to be involved in dilated cardiomyopathy (DCM) [18], but the underlying genetic architecture is currently not understood well. Recently, the evidence level of several genes for their contribution to DCM has been systematically assessed [19]. We specifically analyzed these genes in our Nanopore direct RNA-seq data and demonstrate a better coverage that opens up new opportunities in studying genetics and molecular processes as aberrant splicing underlying DCM pathogenesis.…”