Steven C Greenway1, Ross McLeod2, Stacey Hume3, Nicole M Roslin4, Nanette Alvarez1, Michael Giuffre5, Shing H Zhan6, Yaoqing Shen6, Christoph Preuss7, Gregor Andelfinger7, Steven J M Jones6, Brenda Gerull8. 1. Department of Cardiac Sciences, University of Calgary and Libin Cardiovascular Institute of Alberta, Calgary, Alberta, Canada. 2. Department of Medical Genetics, University of Calgary, Calgary, Alberta, Canada. 3. Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada. 4. The Centre for Applied Genomics, The Hospital for Sick Children Research Institute, Toronto, Ontario, Canada. 5. Department of Pediatrics, University of Calgary, Calgary, Alberta, Canada. 6. Canada's Michael Smith Genome Sciences Centre, Vancouver, British Columbia, Canada. 7. Department of Pediatrics, CHU Sainte-Justine Hospital, Université de Montréal, Montréal, Québec, Canada. 8. 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.
Abstract
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.
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.
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