title: A DNA resequencing array for pathogenic mutation detection in hypertrophic cardiomyopathy.
abstract: 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.
authors.affiliation: Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. siv.fokstuen@medecine.unige.ch
authors.forename: Siv
authors.initials: S
authors.lastname: Fokstuen
authors.forename: Robert
authors.initials: R
authors.lastname: Lyle
authors.forename: Analia
authors.initials: A
authors.lastname: Munoz
authors.forename: Corinne
authors.initials: C
authors.lastname: Gehrig
authors.forename: René
authors.initials: R
authors.lastname: Lerch
authors.forename: Andreas
authors.initials: A
authors.lastname: Perrot
authors.forename: Karl Josef
authors.initials: KJ
authors.lastname: Osterziel
authors.forename: Christian
authors.initials: C
authors.lastname: Geier
authors.forename: Maurice
authors.initials: M
authors.lastname: Beghetti
authors.forename: François
authors.initials: F
authors.lastname: Mach
authors.forename: Juan
authors.initials: J
authors.lastname: Sztajzel
authors.forename: Ulrich
authors.initials: U
authors.lastname: Sigwart
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Blouin
mesh_terms: D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis* / Q000235:genetics; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000175:diagnosis; D004252:DNA Mutational Analysis; D006801:Humans; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis / Q000191:economics / Q000379:methods*