Abstract 11966: Exome Sequencing of Remotely Related Individuals Plus Bioinformatic Analysis Identifies Rbm20 as a Cause Of DCM in a Large Pedigree as Well as Hdac7 a Potential Genetic Modifier
Objective: Whole exome sequencing (WES) was performed in a large, multiplex family with familial dilated cardiomyopathy (DCM) with the intent of identifying a causal variant. Prior commercial testing had been unrevealing. Background: DCM is a significant cause of morbidity and mortality. Up to 50% of DCM cases are familial. Over 30 genes, especially those coding sarcomeric proteins, have been linked to DCM; however, the basis of most cases is unknown. The coding portion of the genome, or exome, is a small segment of the genome, but is enriched for alleles underlying monogenic disorders.
Methods: Exome capture and sequencing was performed in 3 remotely related, affected subjects predicted to have a small fraction of genome identical by descent. Shared variants were filtered for rarity, occurrence in areas of evolutionary conservation, and predicted functional significance. Candidates were validated and tested for segregation by Sanger sequencing. As a complementary method, variants were bioinformatically prioritized using the Variant Annotation Analysis and Search Tool (VAAST).
Results: An average of 91,698 SNPs were identified per subject. There were 7,495 shared heterozygous variants, of which 931 were nonsense, missense, or altered a splice site. Of these, 50 were absent in dbSNP and 1000 Genomes. Only 2 of these were in highly conserved genomic regions. A single variant in RBM20 was absent in internal exomes free of DCM and segregated with disease status. Bioinformatic prioritization supported the results and identified a variant of unknown significance in HDAC7 that appeared to segregate with disease severity among subjects who underwent exome analysis.
Conclusion: WES of remotely related subjects in a large pedigree, followed by systematic filtering, identified the causal mutation of a Mendelian disease without linkage analysis. Bioinformatic tools can assist with variant prioritization. HDAC7 should be investigated as a potential genetic modifier.
- © 2012 by American Heart Association, Inc.