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

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. Genet Med 2010: 12(11):655-667.