Exome Sequencing Identifies a Novel Variant in ACTC1 Associated With Familial Atrial Septal Defect

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• 作者：Steven C. Greenway ; Ross McLeod ; Stacey Hume ; Nicole M. Roslin ; Nanette Alvarez ; Michael Giuffre ; Shing H. Zhan ; Yaoqing Shen ; Christoph Preuss ; Gregor Andelfinger ; FORGE Canada Consortium ; Steven J.M. Jones ; Brenda Gerull
• 刊名：Canadian Journal of Cardiology
• 出版年：February, 2014
• 年：2014
• 卷：30
• 期：2
• 页码：181-187
• 全文大小：618 K

文摘

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, ) 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.