NEONATAL, LETHAL NONCOMPACTION OF THE LEFT-VENTRICULAR MYOCARDIUM IS ALLELIC WITH BARTH-SYNDROME

Loss-of-function mutations in the G4.5 gene have been shown to cause E arth syndrome (BTHS), an X-linked disorder characterized by cardiac an d skeletal myopathy, short stature, and neutropenia. We recently repor ted a family with a severe X-linked cardiomyopathy described as isolat ed noncompaction of the left ventricular myocardium (INVM). Other find ings associated with BTHS (skeletal myopathy, neutropenia, growth reta rdation, elevated urinary organic acids, and mitochondrial abnormaliti es) were either absent or inconsistent, A linkage study of the X chrom osome localized INVM to the Xq28 region near the BTHS locus, suggestin g that these disorders are allelic. We screened the G4.5 gene for muta tions in this family with SSCP and direct sequencing and found a novel glycine-to-arginine substitution at position 197. This position is co nserved in a homologous Caenorhabditis elegans protein. We conclude th at INVM is a severe allelic variant of BTHS with a specific effect on the heart. This finding provides further structure-function informatio n about the G4.5 gene product and has implications for unexplained cas es of severe infantile hypertrophic cardiomyopathy in males.