Exome sequencing identifies a mutation in the ACTN2 gene in a family with idiopathic ventricular fibrillation, left ventricular noncompaction, and sudden death

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: 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.

Figure 1

ALB Family Pedigree. Squares - males; Circles - females; Line through symbol – deceased individual; open symbol with N – clinically unaffected individual; LVNC - left ventricular non-compaction; VF – ventricular fibrillation; DCM – dilated cardiomyopathy; SUD – sudden unexplained death.

Figure 2

ECG and echocardiographic features of the proband (III:5). The ECG (A) shows minimal pathological changes, while the echocardiogram shows (B) LVNC predominantly affecting the left ventricular apex (arrowed) and (C) colour Doppler flow between the trabeculations.

Figure 3

Ventricular fibrillation in relative III:3. Example of a short coupled ventricular ectopic triggering VF, as is typically seen in idiopathic ventricular fibrillation.

Figure 4

Genotyping and haplotype analysis in ALB and EI families. (A) Haplotype analysis in the current Family ALB, (B) DNA sequences of the haplotype, and (C) haplotype analysis in previous Family EI. *inferred haplotype.

Figure 5

Alpha-actinin2 and cardiac disease. Potential mechanisms by which mutations in the ACTN2 gene can lead to diverse cardiac phenotypes.