A DNA Resequencing Array for Pathogenic Mutation Detection in Hypertrophic Cardiomyopathy

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Hypertrophic cardiomyopathy (HCM) is a heterogeneous autosomal dominant cardiac disorder with a prevalence of 1 in 500. Over 450 different pathogenic mutations in at least 16 genes have been identified so far. The large allelic and genetic heterogeneity of HCM requires high-throughput, rapid, and affordable mutation detection technologies to efficiently integrate molecular screening into clinical practice. We developed a custom DNA resequencing array that contains both strands of all coding exons (160), splice-site junctions, and 5′UTR regions of 12 genes that have been clearly implicated in HCM (MYH7,MYBPC3,TNNT2,TPM1,TNNI3,MYL3,MYL2,CSRP3,PLN,ACTC,TNNC1, andPRKAG2). We analyzed a first series of 38 unrelated patients with HCM (17 familial, 21 sporadic). A total of 953,306 bp across the 38 patients were sequenced with a mean nucleotide call rate of 96.92% (range: 93-99.9%). Pathogenic mutations (single nucleotide substitutions) inMYH7,MYBPC3,TNNI3, andMYL3(six known and six novel) were identified in 60% (10/17) of familial HCM and 10% of sporadic cases (2/21). The high-throughput HCM resequencing array is the most rapid and cost-effective tool for molecular testing of HCM to date; it thus has considerable potential in diagnostic and predictive testing, and prognostic stratification. Hum Mutat 29(6), 879-885, 2008.

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