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Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals.

ABSTRACT: Dilated cardiomyopathy (DCM), usually diagnosed as idiopathic dilated cardiomyopathy (IDC), has been shown to have a familial basis in 20-35% of cases. Genetic studies in familial dilated cardiomyopathy (FDC) have shown dramatic locus heterogeneity with mutations identified in >30 mostly autosomal genes showing primarily dominant transmission. Most mutations are private missense, nonsense or short insertion/deletions. Marked allelic heterogeneity is the rule. Although to date most DCM genetics fits into a Mendelian rare variant disease paradigm, this paradigm may be incomplete with only 30-35% of FDC genetic cause identified. Despite this incomplete knowledge, we predict that DCM genetics will become increasingly relevant for genetics and cardiovascular professionals. This is because DCM causes heart failure, a national epidemic, with considerable morbidity and mortality. The fact that early, even pre-symptomatic intervention can prevent or ameliorate DCM, coupled with more cost-effective genetic testing, will drive further progress in the field. Ongoing questions include: whether sporadic (IDC) disease has a genetic basis, and if so, how it differs from familial disease; which gene-specific or genetic pathways are most relevant; and whether other genetic mechanisms (e.g., DNA structural variants, epigenetics, mitochondrial mutations and others) are operative in DCM. We suggest that such new knowledge will lead to novel approaches to the prevention and treatment of DCM.

SUBMITTER: Hershberger RE

PROVIDER: S-EPMC3118426 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals.

Hershberger Ray E RE Morales Ana A Siegfried Jill D JD

Genetics in medicine : official journal of the American College of Medical Genetics 20101101 11

Dilated cardiomyopathy (DCM), usually diagnosed as idiopathic dilated cardiomyopathy (IDC), has been shown to have a familial basis in 20-35% of cases. Genetic studies in familial dilated cardiomyopathy (FDC) have shown dramatic locus heterogeneity with mutations identified in >30 mostly autosomal genes showing primarily dominant transmission. Most mutations are private missense, nonsense or short insertion/deletions. Marked allelic heterogeneity is the rule. Although to date most DCM genetics f ...[more]

PMID: 20864896

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Project description:Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most common referrals in the Inherited Cardiovascular Condition (ICC) Genetics Service. Several issues must be discussed with patients and their families during the genetic consultation session, including the options for genetic testing and cardiovascular surveillance in family members. We developed an ICC registry and performed next-generation-based DNA sequencing for all patients affected by non-syndromic HCM and idiopathic DCM in our joint specialist genetics service. The target gene sequencing panel relied on the Human Phenotype Ontology with 237 genes for HCM (HP:0001639) and 142 genes for DCM (HP:0001644). All subjects were asked to contact their asymptomatic first-degree relatives for genetic counseling regarding their risks and to initiate cardiovascular surveillance and cascade genetic testing. The study was performed from January 1, 2014, to December 31, 2020, and a total of 62 subjects (31-HCM and 31-DCM) were enrolled. The molecular detection frequency was 48.39% (32.26% pathogenic/likely pathogenic, 16.13% variant of uncertain significance or VUS for HCM, and 25.81% (16.13% pathogenic/likely pathogenic, 9.68% VUS) for DCM. The most prevalent gene associated with HCM was MYBPC3. The others identified in this study included ACTN2, MYL2, MYH7, TNNI3, TPM1, and VCL. Among the DCM subjects, variants were detected in two cases with the TTN nonsense variants, while the others were missense and identified in MYH7, DRSP3, MYBPC3, and SCN5A. Following the echocardiogram surveillance and cascade genetic testing in the asymptomatic first-degree relatives, the detection rate of new cases was 8.82% and 6.25% in relatives of HCM and DCM subjects, respectively. Additionally, a new pre-symptomatic relative belonging to an HCM family was identified, although the genomic finding in the affected case was absent. Thus, ICC service is promising for the national healthcare system, aiming to prevent morbidity and mortality in asymptomatic family members.

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Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals.

Publications

Clinical and genetic issues in dilated cardiomyopathy: a review for genetics professionals.

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