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A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy

✍ Scribed by Siv Fokstuen; Robert Lyle; Analia Munoz; Corinne Gehrig; René Lerch; Andreas Perrot; Karl Josef Osterziel; Christian Geier; Maurice Beghetti; François Mach; Juan Sztajzel; Ulrich Sigwart; Stylianos E. Antonarakis; Jean-Louis Blouin

Publisher
John Wiley and Sons
Year
2008
Tongue
English
Weight
227 KB
Volume
29
Category
Article
ISSN
1059-7794

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✦ Synopsis

Communicated by Michel Goossens

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 0 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.

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