Abstract 19823: Whole-Exome Sequencing in an Extended Family with Myocardial Infarction Identified a Potential Functional Mutation in PDE5A
Objective: Despite the enormous success of genome-wide association studies (GWAS), only a small fraction of the expected heritability for CAD and MI is explained so far. One drawback of GWAS is the lack of power to detect rare yet functionally important variants. Rare variants may however cluster in families.
Aim: Studying extended MI-families by means of whole-exome sequencing (WES) may give new insights in the pathophysiology of CAD.
Methods: We analyzed a German MI family with 9 affected and 46 unaffected individuals. We sequenced three distantly related affected family members using the Agilent SureSelect 38 Mb Kit. Variants were validated by Sanger re-sequencing.
Results and Discussion: The three sequenced individuals shared 22,048 variants. Filtering for SNPs with a frequency >1% in dbSNP left 2,845 variants. Of these, 988 variants are conserved (46 Way) and again 772 were located outside of regions of segmental duplication. 23 potentially function-altering variants were left after filtering based on an avsift score >0.05 and ,,HIGH“ effect predicted by Annovar and SNPEFF respectively. To further reduce the number of variants, we focused on those not in dbSNP. This approach left two variants of which only one was successfully validated by Sanger re-sequencing. The variant is a new single nucleotide substitution (A>T) that causes a stop-codon (g.120548312T>A) in the first exon of one of the three known PDE5A transcripts. In addition, the variant lies in a strong regulatory region and may hence also influence transcription. We genotyped all family members available for genetic analysis and found that the variant co-segregates with the disease. Previous independent linkage studies show that the variant lies in a linkage region (LOD=2.63; p=0.0003) which supports the hypothesis that the identified variant is truly disease-causing. To determine whether the variant is found in unrelated individuals we genotyped 2,012 cases and 2,808 controls. Of the cases 0.1% carry the variant, of the controls only 0.03% .
Conclusion: We have in this study identified a new potentially MI-causing variant in the PDE5A gene using WES. Upcoming functional analyses will help us to unravel the disturbed mechanisms and provide us with new insights in the pathogenesis underlying CAD.
- © 2012 by American Heart Association, Inc.