Dataset Information

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human.

ABSTRACT:

Background

Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.

Methods

We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in a spontaneously occurring canine model of DCM. Canine gene discovery was followed up in three human DCM cohorts.

Results

Our results revealed two independent additive loci associated with the typical DCM phenotype comprising left ventricular systolic dysfunction and dilatation. We highlight two novel candidate genes, RNF207 and PRKAA2, known for their involvement in cardiac action potentials, energy homeostasis, and morphology. We further illustrate the distinct genetic etiologies underlying the typical DCM phenotype and ventricular premature contractions. Finally, we followed up on the canine discoveries in human DCM patients and discovered candidate variants in our two novel genes.

Conclusions

Collectively, our study yields insight into the molecular pathophysiology of DCM and provides a large animal model for preclinical studies.

SUBMITTER: Niskanen JE

PROVIDER: S-EPMC10506233 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Publications

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human.

Niskanen Julia E JE Ohlsson Åsa Å Ljungvall Ingrid I Drögemüller Michaela M Ernst Robert F RF Dooijes Dennis D van Deutekom Hanneke W M HWM van Tintelen J Peter JP Snijders Blok Christian J B CJB van Vugt Marion M van Setten Jessica J Asselbergs Folkert W FW Petrič Aleksandra Domanjko AD Salonen Milla M Hundi Sruthi S Hörtenhuber Matthias M Kere Juha J Pyle W Glen WG Donner Jonas J Postma Alex V AV Leeb Tosso T Andersson Göran G Hytönen Marjo K MK Häggström Jens J Wiberg Maria M Friederich Jana J Eberhard Jenny J Harakalova Magdalena M van Steenbeek Frank G FG Wess Gerhard G Lohi Hannes H

Genome medicine 20230918 1

<h4>Background</h4>Dilated cardiomyopathy (DCM) is a life-threatening heart disease and a common cause of heart failure due to systolic dysfunction and subsequent left or biventricular dilatation. A significant number of cases have a genetic etiology; however, as a complex disease, the exact genetic risk factors are largely unknown, and many patients remain without a molecular diagnosis.<h4>Methods</h4>We performed GWAS followed by whole-genome, transcriptome, and immunohistochemical analyses in ...[more]

PMID: 37723491

Similar Datasets

Project description:BackgroundDilated cardiomyopathy (DCM), which is a major cause of heart failure, is a primary cardiac muscle disease with high morbidity and mortality rates. DCM is a genetically heritable disease and more than 10 gene ontologies have been implicated in DCM. CDH2 encodes N-cadherin and belongs to a superfamily of transmembrane proteins that mediate cell-cell adhesion in a calcium-dependent manner. Deficiency of CDH2 is associated with arrhythmogenic right ventricular cardiomyopathy (OMIM: 618920) and agenesis of the corpus callosum, cardiac, ocular, and genital syndrome (OMIM: 618929). However, there have been no reports of isolated DCM associated with CDH2 deficiency.MethodsWe performed whole exome sequencing in a 12-year-old girl with non-syndromic DCM and her unaffected parents. Variants in both known DCM-related genes and novel candidate genes were analyzed and pathogenicity confirmation experiments were performed.ResultsNo pathogenic/likely pathogenic variant in known DCM-related genes was identified in the patient. We found a de novo variant in a candidate gene CDH2 in the patient, namely, c.474G>C/p.Lys158Asn (NM_001792.5). This variant has not been reported in the ClinVar or Human Gene Mutation Database (HGMD). CDH2 p.Lys158Asn was found in the conserved domain of N-cadherin, which is associated with the hydrolysis of the precursor segment and interference with adhesiveness. Furthermore, we tested the expression and efficiency of cell-cell adhesion while overexpressing the CDH2 Lys158Asn mutant and two previously reported variants in CDH2 as positive controls. The adhesion efficiency was considerably reduced in the presence of the mutated CDH2 protein compared with wild-type CDH2 protein, which suggested that the mutated CDH2 protein's adhesion capacity was impaired. The variant was probably pathogenic after integrating clinical manifestations, genetic analysis, and functional tests.ConclusionWe identified a CDH2 variant in DCM. We observed a new clinical symptom associated with N-cadherin deficiency and broadened the genetic spectra of DCM.

Dataset Information

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human.

Background

Methods

Results

Conclusions

Publications

Identification of novel genetic risk factors of dilated cardiomyopathy: from canine to human.

Similar Datasets

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