A systematic analysis of genetic dilated cardiomyopathy reveals numerous ubiquitously expressed and muscle‐specific genes

Harakaľová, Magdaléna; Kummeling, G.J.M.; Sammani, Arjan; Linschoten, Marijke; Baas, Annette F.; Smagt, Jasper van der; Doevendans, Pieter A.; Tintelen, J. Peter van; Dooijes, Dennis; Mokrý, Michal; Asselbergs, Folkert W.

doi:10.1002/ejhf.255

Cited by 59 publications

(53 citation statements)

References 22 publications

(66 reference statements)

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“…On the basis of the notion that proteins specifically expressed in the heart are likely to play a role in cardiac pathophysiology23, we systematically screened the expressed sequence tag (EST) databases for sequences predominantly found in cardiac complementary DNA (cDNA) libraries24. Data extraction relied on the T-STAG (Tissue-Specific Transcripts and Genes; http://tstag.molgen.mpg.de/) and the Unigene (National Center for Biotechnology; http://www.ncbi.nlm.nih.gov/unigene) databases.…”

Section: Resultsmentioning

confidence: 99%

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

et al. 2016

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Calcium signalling plays a critical role in the pathogenesis of heart failure. Here we describe a cardiac protein named Myoscape/FAM40B/STRIP2, which directly interacts with the L-type calcium channel. Knockdown of Myoscape in cardiomyocytes decreases calcium transients associated with smaller Ca2+ amplitudes and a lower diastolic Ca2+ content. Likewise, L-type calcium channel currents are significantly diminished on Myoscape ablation, and downregulation of Myoscape significantly reduces contractility of cardiomyocytes. Conversely, overexpression of Myoscape increases global Ca2+ transients and enhances L-type Ca2+ channel currents, and is sufficient to restore decreased currents in failing cardiomyocytes. In vivo, both Myoscape-depleted morphant zebrafish and Myoscape knockout (KO) mice display impairment of cardiac function progressing to advanced heart failure. Mechanistically, Myoscape-deficient mice show reduced L-type Ca2+currents, cell capacity and calcium current densities as a result of diminished LTCC surface expression. Finally, Myoscape expression is reduced in hearts from patients suffering of terminal heart failure, implying a role in human disease.

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Section: Resultsmentioning

confidence: 99%

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

et al. 2016

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“…Variants were classified in accordance with the American College of Medical Genetics and Genomics (ACMG) guidelines 11 . A virtual cardiomyopathy‐related gene panel was generated that included 409 genes based on the HPO term “cardiomyopathy” (HP:0001638; http://www.human-phenotype-ontology.org/); this panel was supplemented with 10 genes that were not included in this HPO term, but were associated with LVNC (Supplementary Table ) 12 . Putative pathogenic variants in cardiomyopathy‐related genes detected by WES were confirmed by Sanger sequencing with a 3730xl DNA analyzer (Applied Biosystems, Foster City, CA, USA) in the two probands, their parents, and available family members.…”

Section: Methodsmentioning

confidence: 99%

Whole‐exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non‐compaction cardiomyopathy

Sun

Guo

Hao

et al. 2020

Pediatric Investigation

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Importance Pathogenic variants in the RBM20 gene are associated with aggressive dilated cardiomyopathy (DCM). Recently, RBM20 was found to be associated with left ventricular non‐compaction cardiomyopathy (LVNC). Thus far, only five families with LVNC have been reported to carry variants in RBM20. It remains unknown whether the variants in RBM20 associated with DCM can also cause LVNC. Objective To elucidate the causative RBM20 variant in two unrelated patients with both LVNC and DCM, and to identify the clinical characteristics associated with variants in RBM20. Methods Trio whole‐exome sequencing (WES) was performed. Variants were filtered and classified in accordance with the guidelines of the American College of Medical Genetics and Genomics (ACMG). Results We identified two distinct de novo variants in RBM20 (one per patient) in these two patients with LVNC. Both variants have been reported in patients with DCM, without the LVNC phenotype. Patient 1 was an 11‐year‐old girl who had DCM, LVNC, and heart failure; the ratio of noncompacted‐to‐compacted myocardium was 2.7:1. A de novo heterozygous variant c.1907G>A (p.Arg636His) in exon 9 was identified in this patient. Patient 2 was a 13‐year‐old boy who had clinical phenotypes identical to those of Patient 1; the ratio of noncompacted‐to‐compacted myocardium was 3.2:1 in this patient. WES revealed a de novo heterozygous variant c.1909A>G (p.Ser637Gly) in exon 9. Both variants were previously characterized as pathogenic, and our study classified them as pathogenic variants based on the ACMG guidelines. Interpretation We found that two patients with LVNC had variants in RBM20. Our results extended the clinical spectrum of the two RBM20 variants and illustrated that the same variant in RBM20 can cause DCM, with or without the LVNC phenotype.

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“…2015; The Human Gene Mutation Database 2015). Due to latest advances in the field of genetic testing, recent reports have found variants previously associated with DCM to be either nonpathogenic or low‐frequency polymorphisms (Andreasen et al.…”

Section: Introductionmentioning

confidence: 99%

Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy

Nouhravesh

Ahlberg

Ghouse

et al. 2016

Mol Genet Genomic Med

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BackgroundHundreds of genetic variants have been described as disease causing in dilated cardiomyopathy (DCM). Some of these associations are now being questioned. We aimed to identify the prevalence of previously DCM associated variants in the Exome Aggregation Consortium (ExAC), in order to identify potentially false‐positive DCM variants.MethodsVariants listed as DCM disease‐causing variants in the Human Gene Mutation Database were extracted from ExAC. Pathogenicity predictions for these variants were mined from dbNSFP v 2.9 database.ResultsOf the 473 DCM variants listed in HGMD, 148 (31%) were found in ExAC. The expected number of individuals with DCM in ExAC is 25 based on the prevalence in the general population. Yet, 35 variants were found in more than 25 individuals. In 13 genes, we identified all variants previously associated with DCM; four genes contained variants above our estimated cut‐off. Prediction tools found ExAC variants to be significantly more tolerated when compared to variants not found in ExAC (P = 0.004).ConclusionIn ExAC, we identified a higher genotype prevalence of variants considered disease‐causing than expected. More importantly, we found 13 genes in which all variants previously associated with DCM were identified in ExAC, questioning the association of these genes with the monogenic form of DCM.

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A systematic analysis of genetic dilated cardiomyopathy reveals numerous ubiquitously expressed and muscle‐specific genes

Cited by 59 publications

References 22 publications

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

Myoscape controls cardiac calcium cycling and contractility via regulation of L-type calcium channel surface expression

Whole‐exome sequencing reveals two de novo variants in the RBM20 gene in two Chinese patients with left ventricular non‐compaction cardiomyopathy

Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy

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