title: Genetic analysis in post-mortem samples with micro-ischemic alterations.
abstract: Sudden cardiac arrest is a leading cause of death worldwide. Most cardiac arrests happen in patients who have previously suffered a myocardial infarct. The risk of sudden death after infarction may increase in people who carry a pathogenic genetic alteration in cardiac ion channels. We hypothesized that micro-ischemia could trigger lethal arrhythmogenesis, thus we sought to identify genetic alterations in cardiac ion channels in patients with micro-ischemic disease. We studied a cohort of 56 post-mortem samples. Autopsy studies identified myocardial infarction as the cause of death in each case. We used both Sanger sequencing and next-generation sequencing to screen candidate genes associated with sudden cardiac death. We identified six rare missense genetic variations in five unrelated patients. Two variants have been previously reported; one is associated with atrial fibrillation (SCN5A_p.H445D), and the other is predicted to be benign (ANK2_p.T2059M). The novel variants were predicted in silico as benign, except for one (RyR2_p.M4019T), which was classified as deleterious. Our post-mortem, micro-infarction cohort displayed a rate of nearly 10% non-common genetic variants. However, the clinical significance of most of the identified variants remains unknown due to lack of family assessment. Further analyses should be performed in large cohorts to clarify the role of ion-channel gene analysis in samples showing microscopic ischemic alterations.
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Campuzano
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
authors.forename: Olallo
authors.initials: O
authors.lastname: Sanchez-Molero
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Mademont-Soler
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
authors.forename: Monica
authors.initials: M
authors.lastname: Coll
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
authors.forename: Catarina
authors.initials: C
authors.lastname: Allegue
authors.affiliation: Gendiag SL, Barcelona, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Ferrer-Costa
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
authors.forename: Jesus
authors.initials: J
authors.lastname: Mates
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Perez-Serra
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
authors.forename: Bernat
authors.initials: B
authors.lastname: Del Olmo
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Iglesias
authors.affiliation: Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Georgia
authors.initials: G
authors.lastname: Sarquella-Brugada
authors.affiliation: Arrhythmias Unit, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Brugada
authors.affiliation: Histopathology Unit, Instituto Nacional de Toxicología y Ciencias Forenses (INTCF), Barcelona, Spain.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Borondo
authors.affiliation: Forensic Pathology Service, Institut de Medicina Legal i Ciencies Forenses de Catalunya (IMLCFC), Barcelona, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Castella
authors.affiliation: Forensic Pathology Service, Institut de Medicina Legal i Ciencies Forenses de Catalunya (IMLCFC), Barcelona, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Medallo
authors.affiliation: Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain; Cardiology Service, Hospital Josep Trueta, Girona, Spain. Electronic address: ramon@brugada.org.
authors.forename: Ramon
authors.initials: R
authors.lastname: Brugada
mesh_terms: D000328:Adult; D017487:Ankyrins / Q000235:genetics; D001145:Arrhythmias, Cardiac / Q000235:genetics; D015331:Cohort Studies; D016757:Death, Sudden, Cardiac / Q000209:etiology*; D005260:Female; D005787:Gene Frequency; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009124:Muscle Proteins / Q000235:genetics; D020125:Mutation, Missense; D009203:Myocardial Infarction / Q000235:genetics* / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D015221:Potassium Channels / Q000235:genetics; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: C498994:ANK2 protein, human; D017487:Ankyrins; C119587:HCN4 protein, human; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D015221:Potassium Channels; C000621072:RyR2 protein, human; D019837:Ryanodine Receptor Calcium Release Channel; C568320:SCN5A protein, human
keywords: Channelopathies; Genetics; Infarction; Myocardium