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.
Fokstuen
Siv
S
Genetic Medicine, University Hospitals of Geneva, Geneva, Switzerland. siv.fokstuen@medecine.unige.ch
Lyle
Robert
R
Munoz
Analia
A
Gehrig
Corinne
C
Lerch
René
R
Perrot
Andreas
A
Osterziel
Karl Josef
KJ
Geier
Christian
C
Beghetti
Maurice
M
Mach
François
F
Sztajzel
Juan
J
Sigwart
Ulrich
U
Antonarakis
Stylianos E
SE
Blouin
Jean-Louis
JL
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*