title: A Next-Generation Sequencing Approach to Identify Gene Mutations in Early- and Late-Onset Hypertrophic Cardiomyopathy Patients of an Italian Cohort.
abstract: Sequencing of sarcomere protein genes in patients fulfilling the clinical diagnostic criteria for hypertrophic cardiomyopathy (HCM) identifies a disease-causing mutation in 35% to 60% of cases. Age at diagnosis and family history may increase the yield of mutations screening. In order to assess whether Next-Generation Sequencing (NGS) may fulfil the molecular diagnostic needs in HCM, we included 17 HCM-related genes in a sequencing panel run on PGM IonTorrent. We selected 70 HCM patients, 35 with early (≤25 years) and 35 with late (≥65 years) diagnosis of disease onset. All samples had a 98.6% average of target regions, with coverage higher than 20× (mean coverage 620×). We identified 41 different mutations (seven of them novel) in nine genes: MYBPC3 (17/41 = 41%); MYH7 (10/41 = 24%); TNNT2, CAV3 and MYH6 (3/41 = 7.5% each); TNNI3 (2/41 = 5%); GLA, MYL2, and MYL3 (1/41=2.5% each). Mutation detection rate was 30/35 (85.7%) in early-onset and 8/35 (22.9%) in late-onset HCM patients, respectively (p < 0.0001). The overall detection rate for patients with positive family history was 84%, and 90.5% in patients with early disease onset. In our study NGS revealed higher mutations yield in patients with early onset and with a family history of HCM. Appropriate patient selection can increase the yield of genetic testing and make diagnostic testing cost-effective.
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. rubattu.speranza@neuromed.it.|Department of Angiocardioneurology, IRCCS Neuromed, 86077 Pozzilli, Italy. rubattu.speranza@neuromed.it.
authors.forename: Speranza
authors.initials: S
authors.lastname: Rubattu
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. cristina.bozzao@libero.it.
authors.forename: Cristina
authors.initials: C
authors.lastname: Bozzao
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. ariannaermelinda@hotmail.it.
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Pennacchini
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. epagannone@gmail.com.
authors.forename: Erika
authors.initials: E
authors.lastname: Pagannone
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. beatrice.musumeci@uniroma1.it.
authors.forename: Beatrice Maria
authors.initials: BM
authors.lastname: Musumeci
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. maria.piane@uniroma1.it.
authors.forename: Maria
authors.initials: M
authors.lastname: Piane
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. aldo.germani@uniroma1.it.
authors.forename: Aldo
authors.initials: A
authors.lastname: Germani
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. camilla.savio@ospedalesantandrea.it.
authors.forename: Camilla
authors.initials: C
authors.lastname: Savio
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. pietro.francia@uniroma1.it.
authors.forename: Pietro
authors.initials: P
authors.lastname: Francia
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. massimo.volpe@uniroma1.it.|Department of Angiocardioneurology, IRCCS Neuromed, 86077 Pozzilli, Italy. massimo.volpe@uniroma1.it.
authors.forename: Massimo
authors.initials: M
authors.lastname: Volpe
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. camillo.autore@uniroma1.it.
authors.forename: Camillo
authors.initials: C
authors.lastname: Autore
authors.affiliation: Department of Clinical and Molecular Medicine, School of Medicine and Psychology, University Sapienza of Rome, 00185 Rome, Italy. luciana.chessa@uniroma1.it.
authors.forename: Luciana
authors.initials: L
authors.lastname: Chessa
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D002312:Cardiomyopathy, Hypertrophic / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D005820:Genetic Testing; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*
chemical_list: D015415:Biomarkers
keywords: gene variants; genetics; hypertrophic cardiomyopathy; next-generation sequencing