Potentially lethal and heritable cardiomyopathies and cardiac channelopathies are caused by heterogeneous autosomal dominant mutations in over 50 distinct genes, and multiple genes are responsible for a given disease. Clinical genetic tests are available for several of the inherited cardiac diseases and clinical investigations guide which test to order. This study describes a family with cardiac disease in which marked clinical diversity exists. In the absence of a unified clinical diagnosis, we used exome sequencing to identify a causal mutation.

Clinical evaluation of family members was performed, including physical examination, electrocardiography, 2D transthoracic echocardiography and review of autopsy records. Exome sequencing was performed on a clinically affected individual and co-segregation studies and haplotype analysis were performed to further confirm pathogenicity.

Clinically affected members showed marked cardiac phenotype heterogeneity. While some individuals were asymptomatic, other presentations included left ventricular non-compaction, a resuscitated cardiac arrest due to idiopathic ventricular fibrillation, dilated cardiomyopathy, and sudden unexplained death. Whole exome sequencing identified an Ala119Thr mutation in the alpha-actinin-2 (ACTN2) gene that segregated with disease. Haplotype analysis showed that this mutation segregated with an identical haplotype in a second, previously described family with clinically diverse cardiac disease, and is likely inherited from a common ancestor.

Mutations in the ACTN2 gene can be responsible for marked cardiac phenotype heterogeneity in families. The diverse mechanistic roles of ACTN2 in the cardiac Z-disc may explain this heterogeneous clinical presentation. Exome sequencing is a useful adjunct to cardiac genetic testing in families with mixed clinical presentations.