Novel Gene Mutations in Patients With Left Ventricular Noncompaction or Barth Syndrome

TLDR

Mutations in G4.5 cause a spectrum of severe infantile cardiomyopathies, including isolated left ventricular noncompaction and Barth syndrome with dilated cardiomyopathy. The study aimed to investigate LVNC or Barth syndrome patients for mutations in G4.5 and other novel genes. DNA from affected families and individuals was screened for mutations using single‑strand conformation polymorphism analysis and sequencing. The study identified a novel α‑dystrobrevin P121L mutation in LVNC with CHD and multiple G4.5 mutations—including missense, splice donor, splice acceptor, and a premature stop—across families with LVNC and Barth syndrome, demonstrating genetic heterogeneity and a broad cardiomyopathy spectrum.

Abstract

Background —Mutations in the gene G4.5 result in a wide spectrum of severe infantile cardiomyopathic phenotypes, including isolated left ventricular noncompaction (LVNC), as well as Barth syndrome (BTHS) with dilated cardiomyopathy (DCM). The purpose of this study was to investigate patients with LVNC 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 families with BTHS associated with LVNC or DCM, and screened for mutations by single-strand DNA conformation polymorphism analysis and DNA sequencing. In 1 family with LVNC and CHD, a C→T mutation was identified at nucleotide 362 of α -dystrobrevin , changing a proline to leucine (P121L). Mutations in G4.5 were identified in 2 families with isolated LVNC: a missense mutation 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 mutation 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 identified in a sporadic case of BTHS. Conclusions —These data demonstrate genetic heterogeneity in LVNC, with mutation of a novel gene, α -dystrobrevin , identified in LVNC associated with CHD. In addition, these results confirm that mutations in G4.5 result in a wide phenotypic spectrum of cardiomyopathies.