We sought to define the pathogenic mutation in a family with hypertrophic cardiomyopathy (HC) and a markedly arrhythmogenic phenotype. The proband was an 8-year-old female with a sentinel event of sudden death. Screening echocardiograms revealed HC in 2 of her 3 siblings and her father. Her youngest male sibling was diagnosed with HC at age 2 years and died suddenly at age 6 years from ventricular fibrillation despite an implanted cardioverter defibrillator. Using DNA extracted from peripheral lymphocytes, linkage exclusion was performed by haplotype analysis of polymorphic markers for the HC genes. Genes not excluded by linkage were analyzed for mutations using denaturing high-performance liquid chromatography (DHPLC) and direct DNA sequencing. Using this strategy, a 610 T>G nucleotide substitution in the α-tropomyosin gene (TPM1) was identified resulting in a novel L185R (Leucine [L] to Arginine [R]) missense mutation. This mutation was a spontaneous germ-line mutation originating in the proband's father. L185R-TPM1 cosegregated with family members having clinical evidence of HC, including the proband as confirmed by molecular autopsy. The mutation was not present in 400 reference alleles. Thus, a novel missense mutation in TPM1 was discovered in a family with HC and sudden death in childhood. Unlike previously defined mutations that may disrupt the interactions between α-tropomyosin monomers, the L185R mutation may affect troponin-T binding. Defining the pathogenic mutation enabled definitive molecular diagnosis of 2 surviving children.
ASJC Scopus subject areas
- Cardiology and Cardiovascular Medicine