title: Rare Titin (TTN) Variants in Diseases Associated with Sudden Cardiac Death.
abstract: A leading cause of death in western countries is sudden cardiac death, and can be associated with genetic disease. Next-generation sequencing has allowed thorough analysis of genes associated with this entity, including, most recently, titin. We aimed to identify potentially pathogenic genetic variants in titin. A total of 1126 samples were analyzed using a custom sequencing panel including major genes related to sudden cardiac death. Our cohort was divided into three groups: 432 cases from patients with cardiomyopathies, 130 cases from patients with channelopathies, and 564 post-mortem samples from individuals showing anatomical healthy hearts and non-conclusive causes of death after comprehensive autopsy. None of the patients included had definite pathogenic variants in the genes analyzed by our custom cardio-panel. Retrospective analysis comparing the in-house database and available public databases also was performed. We identified 554 rare variants in titin, 282 of which were novel. Seven were previously reported as pathogenic. Of these 554 variants, 493 were missense variants, 233 of which were novel. Of all variants identified, 399 were unique and 155 were identified at least twice. No definite pathogenic variants were identified in any of genes analyzed. We identified rare, mostly novel, titin variants that seem to play a potentially pathogenic role in sudden cardiac death. Additional studies should be performed to clarify the role of these variants in sudden cardiac death.
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. oscar@brugada.org.|Medical Science Department, School of Medicine, University of Girona, Girona 17071, Spain. oscar@brugada.org.
authors.forename: Oscar
authors.initials: O
authors.lastname: Campuzano
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. osanchezmolero@gencardio.com.
authors.forename: Olallo
authors.initials: O
authors.lastname: Sanchez-Molero
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. imademont@gencardio.com.
authors.forename: Irene
authors.initials: I
authors.lastname: Mademont-Soler
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. hriuro@gencardio.com.
authors.forename: Helena
authors.initials: H
authors.lastname: Riuró
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. callegue@gencardio.com.
authors.forename: Catarina
authors.initials: C
authors.lastname: Allegue
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. mcoll@gencardio.com.
authors.forename: Monica
authors.initials: M
authors.lastname: Coll
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. aperez@gencardio.com.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pérez-Serra
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. jmates@gencardio.com.
authors.forename: Jesus
authors.initials: J
authors.lastname: Mates
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. ferran.pico@gencardio.com.
authors.forename: Ferran
authors.initials: F
authors.lastname: Picó
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. annai@brugada.org.
authors.forename: Anna
authors.initials: A
authors.lastname: Iglesias
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona 17190, Spain. ramon@brugada.org.|Medical Science Department, School of Medicine, University of Girona, Girona 17071, Spain. ramon@brugada.org.|Cardiovascular Genetics Clinic, Hospital Josep Trueta, Girona 17007, Spain. ramon@brugada.org.
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
mesh_terms: D001483:Base Sequence; D016022:Case-Control Studies; D064211:Connectin / Q000235:genetics*; D016757:Death, Sudden, Cardiac; D006331:Heart Diseases / Q000235:genetics* / Q000473:pathology; D006801:Humans; D054643:INDEL Mutation; D008969:Molecular Sequence Data; D020125:Mutation, Missense
chemical_list: D064211:Connectin; C577285:TTN protein, human
keywords: forensics; genetics; juvenile; next-generation sequencing; pediatric; sudden cardiac death; titin