Genetic analysis in patients with left ventricular noncompaction and evidence for genetic heterogeneity

Left ventricular noncompaction (LVNC) is a cardiomyopathy characterized by numerous excessively trabeculations and deep intertrabecular recesses. This study was performed to investigate Japanese LVNC patients for disease-causing mutations in a series of selected candidate genes. DNA was isolated from the peripheral blood of 79 cases including 20 familial cases and 59 sporadic cases. DNA samples were screened for mutations in the genes encoding G4.5 (TAZ), alpha-dystrobrevin (DTNA), alpha1-syntrophin (SNTA1), FK506 Binding protein 1A (FKBP1A or FKPB12: FKBP1A), and LIM Domain Binding protein 3 (Cypher/ZASP: LDB3), using single-strand conformational polymorphism analysis and DNA sequencing. DNA variants were identified in 6 of the 79 cases, including four familial cases and two sporadic cases. A splice acceptor mutation of intron 8 in TAZ (IVS8-1G>C) was identified in one family with isolated LVNC, resulting in deletion of exon 9 from mRNA. In a sporadic case of isolated LVNC and Barth syndrome (BTHS), a 158insC in exon 2 of TAZ resulting in a frame-shift mutation was identified. A 1876G>A substitution changing an aspartic acid to asparagine (D626N) was identified in LDB3 in four members of two families with LVNC. A 163G>A polymorphism was identified in LDB3, which changed a valine to isoleucine (V55I) in one patient with isolated LVNC. In addition, in a family with nonisolated LVNC, a 362C>T mutation was identified in DTNA. LVNC, like other forms of inherited cardiomyopathy, is a genetically heterogeneous disease, associated with variable clinical symptoms and can be inherited as an autosomal or X-linked recessive disorder.