Abstract 15808: Whole Exome Sequencing and Hypertrophic Cardiomyopathy
Background: Hypertrophic cardiomyopathy (HCM) is a common cause of sudden death in young people and a source of morbidity and mortality in patients of all ages. Targeted sequencing identifies the genetic basis for this disease in ~35-60% of affected individuals. Whole exome sequencing, with its broad coverage on human exons, offers superior sensitivity and may provide novel insight into the pathogenesis of the disorder.
Methods: We performed whole-exome sequencing on six related subjects in whom target sequencing had not identified a pathogenic mutation: four with manifest HCM, one obligate carrier, and one unaffected adult. First, we excluded common, benign polymorphisms using a combination of publicly available controls from the 1000 genomes variation database, dbSNP, and sequence data from our laboratory. Second, we used a novel phasing algorithm to identify candidate haplotypes, or sets of variants that are transmitted together on one chromosome, across the three generation pedigree to narrow the search space for pathogenic variants. Non-synonymous or splice disrupting single nucleotide variants (SNVs), and frameshift coding indels (NS/SS/FI) were scored for evolutionary conservation using multiple sequence alignment of 46 mammalian species.
Results: Sequence data was successfully generated for 97.9% of targeted exonic regions at an average read depth of 134x. We identified 12,649 NS/SS/FI variants in the pedigree, and 892 of these variants were not seen in population controls. Thirty-six of these private variants co-segregated in affected individuals and were absent in the unaffected subject. One SNV, which occurred at the most evolutionarily conserved locus of all affected nucleotides, resulted in a protein-altering change in the gene encoding a spectrin repeat nuclear envelope protein. This gene has been previously implicated in dilated cardiomyopathy but with no established role in HCM.
Conclusions: Whole exome sequencing in families can be combined with population variation, evolutionary conservation, and linkage data for pathogenic gene identification in HCM. Experimental confirmation of the functional role of this variant may implicate the spectrin repeat containing nuclear envelope assembly in the pathogenesis of HCM.
- © 2011 by American Heart Association, Inc.