title: Genetic analysis, in silico prediction, and family segregation in long QT syndrome.
abstract: The heritable cardiovascular disorder long QT syndrome (LQTS), characterized by prolongation of the QT interval on electrocardiogram, carries a high risk of sudden cardiac death. We sought to add new data to the existing knowledge of genetic mutations contributing to LQTS to both expand our understanding of its genetic basis and assess the value of genetic testing in clinical decision-making. Direct sequencing of the five major contributing genes, KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2, was performed in a cohort of 115 non-related LQTS patients. Pathogenicity of the variants was analyzed using family segregation, allele frequency from public databases, conservation analysis, and Condel and Provean in silico predictors. Phenotype-genotype correlations were analyzed statistically. Sequencing identified 36 previously described and 18 novel mutations. In 51.3% of the index cases, mutations were found, mostly in KCNQ1, KCNH2, and SCN5A; 5.2% of cases had multiple mutations. Pathogenicity analysis revealed 39 mutations as likely pathogenic, 12 as VUS, and 3 as non-pathogenic. Clinical analysis revealed that 75.6% of patients with QTc≥500 ms were genetically confirmed. Our results support the use of genetic testing of KCNQ1, KCNH2, and SCN5A as part of the diagnosis of LQTS and to help identify relatives at risk of SCD. Further, the genetic tools appear more valuable as disease severity increases. However, the identification of genetic variations in the clinical investigation of single patients using bioinformatic tools can produce erroneous conclusions regarding pathogenicity. Therefore segregation studies are key to determining causality.
authors.affiliation: 1] Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain [2] Department of Medical Sciences, Medical School, Universitat de Girona, Girona, Spain.
authors.forename: Helena
authors.initials: H
authors.lastname: Riuró
authors.affiliation: 1] Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain [2] Department of Medical Sciences, Medical School, Universitat de Girona, Girona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Campuzano
authors.affiliation: Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Paola
authors.initials: P
authors.lastname: Berne
authors.affiliation: Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Arbelo
authors.affiliation: 1] Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain [2] Department of Medical Sciences, Medical School, Universitat de Girona, Girona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Iglesias
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Pérez-Serra
authors.affiliation: 1] Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain [2] Institute of Forensic Medicine, Catholic University, Rome, Italy.
authors.forename: Mònica
authors.initials: M
authors.lastname: Coll-Vidal
authors.affiliation: Institute of Forensic Medicine, Catholic University, Rome, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Partemi
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Mademont-Soler
authors.affiliation: Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain.
authors.forename: Ferran
authors.initials: F
authors.lastname: Picó
authors.affiliation: 1] Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain [2] Department of Medical Sciences, Medical School, Universitat de Girona, Girona, Spain.
authors.forename: Catarina
authors.initials: C
authors.lastname: Allegue
authors.affiliation: Institute of Forensic Medicine, Catholic University, Rome, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Oliva
authors.affiliation: UCSF School of Medicine, San Francisco, CA, USA.
authors.forename: Edward
authors.initials: E
authors.lastname: Gerstenfeld
authors.affiliation: Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Georgia
authors.initials: G
authors.lastname: Sarquella-Brugada
authors.affiliation: Hospital Puerta de Hierro, Madrid, Spain.
authors.forename: Víctor
authors.initials: V
authors.lastname: Castro-Urda
authors.affiliation: Hospital Puerta de Hierro, Madrid, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Fernández-Lozano
authors.affiliation: Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Lluís
authors.initials: L
authors.lastname: Mont
authors.affiliation: Hospital Clínic de Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Brugada
authors.affiliation: 1] Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain [2] Department of Medical Sciences, Medical School, Universitat de Girona, Girona, Spain.
authors.forename: Fabiana S
authors.initials: FS
authors.lastname: Scornik
authors.affiliation: 1] Cardiovascular Genetics Center, Institut d'Investigació Biomèdica de Girona, Girona, Spain [2] Department of Medical Sciences, Medical School, Universitat de Girona, Girona, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
mesh_terms: D000293:Adolescent; D000328:Adult; D019295:Computational Biology; D005260:Female; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D051656:KCNQ Potassium Channels / Q000235:genetics; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D061566:Voltage-Gated Sodium Channels / Q000235:genetics; D055815:Young Adult
chemical_list: D051656:KCNQ Potassium Channels; D061566:Voltage-Gated Sodium Channels