title: Next Generation Sequencing and Linkage Analysis for the Molecular Diagnosis of a Novel Overlapping Syndrome Characterized by Hypertrophic Cardiomyopathy and Typical Electrical Instability of Brugada Syndrome.
abstract: BACKGROUND
  Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant inherited disorder; mutations in at least 20 genes have been associated. Brugada syndrome (BrS) is an autosomal dominant inherited disorder caused by mutations mainly in theSCN5Agene. A new clinical entity that consists of HCM, typical electrical instability of BrS and sudden death (SD), is described.
  
  
  RESULTS
  The family was constituted by 7 members, 4 of who presented clinical features of HCM and electrical instability of BrS. The clinical presentation of proband was ventricular fibrillation. All members were clinically evaluated by physical examination, 12-lead electrocardiography, 2-dimensional echocardiography, stress test, electrocardiogram Holter, flecainide test, and electrophysiological study. An integrated linkage analysis and next generation sequencing (NGS) approach was used to identify the causative mutation. Linkage with the α-tropomyosin (TPM1) gene on chromosome 15q22 was identified. The NGS study identified a missense mutation within theTPM1gene (c.574G>A; p.E192K), exactly located in a binding domain with polycystin-2 protein. No other pathogenic mutations were identified.
  
  
  CONCLUSIONS
  This is the first report of an association between HCM and BrS, and the first to use a combined approach of linkage and NGS to identify a causative mutation in SD. The present study expands the clinical spectrum of disorders associated with theTPM1gene and may be useful to report novel mechanisms of electrical instability in HCM and BrS.
authors.affiliation: Department of Emergency and Critical Care, Section of Cardiology, Policlinic of Tor Vergata.
authors.forename: Ruggiero
authors.initials: R
authors.lastname: Mango
authors.forename: Andrea
authors.initials: A
authors.lastname: Luchetti
authors.forename: Raffaele
authors.initials: R
authors.lastname: Sangiuolo
authors.forename: Valentina
authors.initials: V
authors.lastname: Ferradini
authors.forename: Nicola
authors.initials: N
authors.lastname: Briglia
authors.forename: Emiliano
authors.initials: E
authors.lastname: Giardina
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Ferrè
authors.forename: Manuela
authors.initials: M
authors.lastname: Helmer Citterich
authors.forename: Francesco
authors.initials: F
authors.lastname: Romeo
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
authors.forename: Federica
authors.initials: F
authors.lastname: Sangiuolo
mesh_terms: D000328:Adult; D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000503:physiopathology; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics*; D004562:Electrocardiography; D005260:Female; D008040:Genetic Linkage; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D008875:Middle Aged; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D014335:Tropomyosin / Q000235:genetics*
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human; C490775:TPM1 protein, human; D014335:Tropomyosin