The genetics of dilated cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is a leading cause for cardiac transplantation with an estimated prevalence of 36.5 per 100,000 individuals in the USA.  DCM is a disorder characterized by ventricular dilation and systolic contractile dysfunction.  It is the result of a heterogenous group of inherited and acquired disorders and is an important cause of heart failure.  Idiopathic DCM is the most common cause of DCM and accounts for ~50% of cases with a familial basis found in up to 35%. A genome wide screen in four generations of a Puerto Rican kindred with autosomal dominant isolated familial dilated cardiomyopathy (FDCM) was conducted.  Two-point linkage analysis mapped the disease locus to chromosome 14q11.2-13 (lod score = 5.11 at q  = 0).  The b-myosin heavy chain (b-MHC) candidate gene mapped to this region and direct sequencing identified a single nucleotide T168C mutation (Ser®Pro532) which was highly conserved across a range of different species.  A novel mismatch primer that converted the half-site to a full recognition site for the SphI endonuclease independently confirmed the mutation and its absence in 192 normal chromosomes.  A further disease causing mutation 2378C ®G  replacing Phe764Leu in b-MHC was identified in an unrelated family.  A further two unrelated FDCM families were found to have deleted one of four tandem lysine residues (DLys210) of the cardiac troponin T gene. Understanding the monogenic disorders provides us with important knowledge not only about the rare condition being studied but also about potential mechanisms underlying the more common phenotypes.  This finding may open up novel and perhaps unpredictable therapeutic targets.EThOS - Electronic Theses Online ServiceGBUnited Kingdo