Abstract 17686: Hunting for Novel Dilated Cardiomyopathy Genes using Haplotype Sharing and Exome Sequencing
Background: Idiopathic Dilated cardiomyopathy (DCM) is a heritable, monogenic disorder in one-third of cases and is characterized by dilation and impaired contraction of the left ventricle. DCM is genetically highly heterogeneous and more than 40 genes are known to be involved. Mutations in these genes can be identified in around 30% of index-patients. To identify novel DCM genes we used an approach in which the Haplotype Sharing Test (HST) and exome sequencing were combined. Haplotype sharing has been shown to be a powerful tool for identifying candidate regions and disease-causing genes. Moreover, exome sequencing was shown to be effective in the identification of novel genes in monogenic disorders.
Methods: To localize novel DCM genes, 250K SNP genotyping was used to identify shared haplotypes between patients from a single pedigree. The HST was applied to (I) a family with 6 DCM patients and (II) a family with 3 DCM patients and 1 patient with reduced left ventricular function, yet not fulfilling formal DCM criteria. To subsequently identify the corresponding disease genes, exome sequencing using DNA of the probands of both families was performed.
Results: The HST revealed a shared haplotype of 71 cM on chromosome 15, containing ∼600 genes in family I and a 46 cM haplotype on chromosome 9, containing ∼475 genes in family II. Upon exclusion of known DCM genes within these regions, exome sequencing revealed several potentially pathogenic variants in both families. Carriership analysis in family members, healthy controls and mutation analysis in our DCM cohort is in progress.
Conclusions: We identified potentially pathogenic variants in candidate regions in two DCM families. Our results show that using a combined approach of the HST and exome sequencing is highly promising in identifying mutations in novel genes underlying inherited cardiomyopathies.
- © 2010 by American Heart Association, Inc.