Dilated Cardiomyopathy 1AA
In 4 affected members over 2 generations of an Australian family with marked cardiac phenotype heterogeneity, including dilated cardiomyopathy (CMD1AA; 612158), left ventricular noncompaction, ventricular fibrillation, and sudden death, Bagnall et al. (2014) identified heterozygosity for a G-A transition in the ACTN2 gene (chr1.236,882,307G-A, GRCh37), resulting in an ala119-to-thr (A119T) substitution. The mutation was also present in an asymptomatic 35-year-old female cousin of the proband, in whom cardiac evaluation at age 29 was normal, including electrocardiography, echocardiography, electrophysiologic study, and 7-day Holter monitor. Haplotype analysis was consistent with a common ancestor shared by this family and the Australian family reported by Chiu et al. (2010).
Familial Hypertrophic Cardiomyopathy 23
In affected members of a large 3-generation Australian family with clinically heterogeneous CMH mapping to chromosome 1 (CMH23; see 612158), Chiu et al. (2010) identified heterozygosity for a G-A transition in exon 3 of the ACTN2 gene, resulting in an A119T substitution at a highly conserved residue within the CH1 domain of the actin-binding domain. Overexpression of the A119T variant in stably transfected myoblast cells resulted in a significant increase in RNA markers of hypertrophy. Chiu et al. (2010) stated that in contrast to previously reported patients with ACTN2 mutations Theis et al. (2006), none of these patients displayed sigmoidal morphology; rather, they exhibited generally mild hypertrophy with a diverse distribution, involving the septum in some individuals, whereas others showed apical, concentric, or right ventricular hypertrophy, with progression to a dilated phenotype and severe heart failure in some cases.
