A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy

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 , and PRKAG2 ). 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) in MYH7, MYBPC3, TNNI3 , and MYL3 (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. © 2008 Wiley‐Liss, Inc.