Novel gene mutations in patients with left ventricular noncompaction or Barth syndrome

Background-Mutations in the gene G4.5 result in a wide spectrum of severe i nfantile cardiomyopathic phenotypes, including isolated left ventricular no ncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyo pathy (DCM). The purpose of this study was to investigate patients with LVN C or BTHS for mutations in G4.5 or other novel genes. Methods and Results-DNA was isolated from 2 families and 3 individuals with isolated LVNC or LVNC with congenital heart disease (CHD), as well as 4 fa milies with BTHS associated with LVNC or DCM, and screened for mutations by single-strand DNA conformation polymorphism analysis and DNA sequencing. I n 1 family with LVNC and CHD, a C-->T mutation was identified at nucleotide 362 of alpha -dystrobrevin, changing a proline to leucine (P121L). Mutatio ns in G4.5 were identified in 2 families with isolated LVNC: a missense mut ation in exon 4 (C118R) in 1 and a splice donor mutation (IVS10+2T-->A) in intron 10 in the other. In a family with cardiomyopathies ranging from BTHS or fatal infantile cardiomyopathy to asymptomatic DCM, a splice acceptor m utation in exon 2 of G4.5 (398-2 A-->G) was identified, and a 1-bp deletion in exon 2 of G4.5, resulting in a stop codon after amino acid 41, was iden tified in a sporadic case of BTHS. Conclusions-These data demonstrate genetic heterogeneity in LVNC, with muta tion of a novel gene, alpha -dystrobrevin, identified in LVNC associated wi th CHD. In addition. these results confirm that mutations in G4.5 result in a wide phenotypic spectrum of cardiomyopathies.