Novel Alpha-Actinin 2 Variant Associated with Familial Hypertrophic Cardiomyopathy and Juvenile Atrial Arrhythmias: A Massively Parallel Sequencing Study
Background—Next generation sequencing (NGS) might be particularly advantageous in genetically heterogeneous conditions, such as hypertrophic cardiomyopathy (HCM), in which a considerable proportion of patients remains undiagnosed following Sanger. In this study we present an Italian family with atypical HCM in which a novel disease-causing variant in alpha-actinin 2 (ACTN2) was identified by NGS.
Methods and Results—A large family spanning four generations was examined, exhibiting an autosomal dominant cardiomyopathic trait comprising a variable spectrum of a) mid-apical HCM with restrictive evolution with marked bi-atrial dilatation, b) early onset atrial fibrillation and atrioventricular block, and c) left ventricular (LV) noncompaction. In the proband, 48 disease-genes for HCM, selected on the basis of published reports, were analysed by targeted resequencing with a customized enrichment system. Following bioinformatics analysis, four likely pathogenic variants were identified: TTN c.21977G>A (p.Arg7326Gln); TTN c.8749A>C (p.Thr2917Pro); ACTN2 c.683T>C (p.Met228Thr) and OBSCN c.13475T>G (p.Leu4492Arg). The novel variant ACTN2 c.683T>C (p.Met228Thr), located in the Actin-binding domain, proved to be the only mutation fully co-segregating with the cardiomyopathic trait in 18 additional family members (of whom 11 clinically affected). ACTN2 c.683T>C (p.Met228Thr) was absent in 570 alleles of healthy controls and in 1000 Genomes Project, and was labelled as "Damaging" by in silico analysis using PolyPhen-2, as "Deleterious" by SIFT and as "Disease-Causing" by Mutation Taster.
Conclusions—A targeted NGS approach allowed the identification of a novel ACTN2 variant associated with mid-apical HCM and juvenile onset of atrial fibrillation, emphasizing the potential of such approach in HCM diagnostic screening.
- next generation sequencing
- familial atrial fibrillation
- actinin 2 gene
- gene mutation
- genetic heart disease
- genetic testing
- genomic study
- hypertrophic cardiomyopathy
- Received December 20, 2013.
- Revision received June 25, 2014.
- Accepted June 30, 2014.