Exome sequencing identifies a novel variant in ACTC1 associated with familial atrial septal defect.
BACKGROUND
The genetics of congenital heart disease (CHD) remain incompletely understood. Exome sequencing has been successfully used to identify disease-causing mutations in familial disorders in which candidate gene analyses and linkage mapping have failed.


METHODS
We studied a large family characterized by autosomal dominant isolated secundum atrial septal defect (ASD) (MIM No. 612794). Candidate gene resequencing and linkage analysis were uninformative.


RESULTS
Whole-exome sequencing of 2 affected family members identified 44 rare shared variants, including a nonsynonymous mutation (c.532A>T, p.M178L, NM_005159.4) in alpha-cardiac actin (ACTC1). This mutation was absent from 1834 internal controls as well as from the 1000 Genomes and the Exome Sequencing Project (ESP) databases, but predictions regarding its effect on protein function were divergent. However, p.M178L was the only rare mutation segregating with disease in our family.


CONCLUSIONS
Our results provide further evidence supporting a causative role for ACTC1 mutations in ASD. Massively parallel sequencing of the exome allows for the detection of novel rare variants causing CHD without the limitations of a candidate gene approach. When mutation prediction algorithms are not helpful, studies of familial disease can help distinguish rare pathologic mutations from benign variants. Consideration of the family history can lead to genetic insights into CHD.
Department of Cardiac Sciences, University of Calgary and Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
Steven C
SC
Greenway
Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada.
Ross
R
McLeod
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Stacey
S
Hume
The Centre for Applied Genomics, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada.
Nicole M
NM
Roslin
Department of Cardiac Sciences, University of Calgary and Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada.
Nanette
N
Alvarez
Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada.
Michael
M
Giuffre
Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
Shing H
SH
Zhan
Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
Yaoqing
Y
Shen
Department of Pediatrics, CHU Sainte-Justine Hospital, Université de Montréal, Montréal, Québec, Canada.
Christoph
C
Preuss
Department of Pediatrics, CHU Sainte-Justine Hospital, Université de Montréal, Montréal, Québec, Canada.
Gregor
G
Andelfinger
Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada.
Steven J M
SJ
Jones
Department of Cardiac Sciences, University of Calgary and Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada; Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada. Electronic address: bgerull@ucalgary.ca.
Brenda
B
Gerull
D000199:Actins / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004247:DNA / Q000235:genetics*; D059472:Exome; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006344:Heart Septal Defects, Atrial / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D017422:Sequence Analysis, DNA; D055815:Young Adult
C526913:ACTC1 protein, human; D000199:Actins; D004247:DNA