Abstract 1924: Identification of Novel Mutations in Dilated Cardiomyopathy Using the Haplotype Sharing Test
Background: Idiopathic Dilated Cardiomyopathy (DCM) is a heritable disorder in 30% of cases and is characterized by dilation and impaired contraction of the left ventricle. We have previously shown that haplotype sharing is a powerful tool for identifying disease-causing genes. Since DCM is genetically highly heterogeneous, with >35 genes involved, the Haplotype Sharing Test (HST) can be used as a pre-screening method to identify a candidate region. After using the HST, we found novel mutations in the sarcomeric proteins alpha-tropomyosin (TPM1) and beta cardiac myosin heavy chain (MYH7) in familial DCM.
Methods: The HST was designed, using high density SNP genotyping data, to identify the largest possibly shared haplotypes between patients that are members of a pedigree. We applied the HST to:
a family with 11 DCM patients using 250K SNP arrays in 6 patients.
a family with 8 DCM patients using 610K SNP arrays in all patients.
Results: In family 1, the HST revealed a largest shared haplotype of 408 consecutive SNPs on chromosome 15, corresponding with a 6,5 cM genomic region and containing 90 genes. We identified a novel missense mutation in TPM1 in all affected family members. In family 2, the HST revealed a largest shared haplotype of 2707 consecutive SNPs on chromosome 14, corresponding with a 20,8 cM genomic region and containing 239 genes. We identified a novel missense mutation in MYH7 in all affected family members. Both mutations were absent in >150 ethnically matched controls, co-segregate with the disease and change highly conserved residues, indicating a pathogenic nature.
Conclusions: We identified novel mutations in TPM1 and MYH7 causing DCM. Our results show that using the HST, with subsequent testing of candidate genes in the region containing the largest haplotype, is a highly efficient method to identify mutations underlying the cardiomyopathy.