Abstract 13350: Exome Sequencing Identifies a Novel Variant in ACTC1 Segregating in a Family with Atrial Septal Defects
Atrial septal defect (ASD) is one of the most common congenital heart defects with variable phenotypic expression. Very few families with isolated ASDII and autosomal dominant inheritance have been described with mutations in genes encoding transcriptional factors as well as the alpha-cardiac actin (ACTC1). Recently a founder mutation in ACTC1 (p.M123V) was identified in two Swedish families.
Here we present a family with autosomal dominant isolated secundum ASD diagnosed in 6 individuals with a variable range of shunt sizes between 5 mm and 22 mm. Five individuals underwent surgical repair in early childhood. None of the affected individuals has had additional findings such as congenital heart defects or cardiomyopathy.
The family is part of the FORGE project. For two distantly related individuals of this family, we captured and sequenced the exomes using the Illumina HiSeq2000 machines. Post-quality control reads were aligned to the reference human genome (hg18) using Burrows-Wheeler Aligner and then variant-called using SAMtools utilities. Only variants inside protein-coding regions defined by Ensembl gene models were retained for downstream analysis. A set of 44 shared putative disease causative variants was identified after filtering against dbSNP, 1000 Genomes, and an in-house database of normal germ-line variants (1834 genomes/exomes combined). Further co-segregation studies revealed that only the heterozygous c.532A>T variant in the ACTC1 gene leading to an amino acid substitution of p.M178L segregates in affected individuals and one obligate carrier suggesting its causative role for ASDII in this family.
Although the Met178 residue is highly conserved among different actins and species, the substitution to leucine involves a conservative change of hydrophobic amino acids which is a favored substitution rather than a deleterious one. Furthermore software tools predict the possible impact of this change on the structure and function of the ACTC1 protein to be benign. However, this has been observed in a similar way for the previously identified p.M123V founder mutation. Further evaluation of the ACTC1 gene in larger cohorts of familiar and sporadic ASDs is ongoing to determine the role of genetic variants in ACTC1 for ASD.
- © 2012 by American Heart Association, Inc.