title: Phenotype-driven molecular autopsy for sudden cardiac death.
abstract: A phenotype-driven approach to molecular autopsy based in a multidisciplinary team comprising clinical and laboratory genetics, forensic medicine and cardiology is described. Over a 13 year period, molecular autopsy was undertaken in 96 sudden cardiac death cases. A total of 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. Seven (15%) had likely pathogenic variants in ion channelopathy genes [KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)]. Fifty cases aged between 2 and 67 had a cardiomyopathy. Twenty-five had arrhythmogenic right ventricular cardiomyopathy (ARVC), 10 dilated cardiomyopathy (DCM) and 15 hypertrophic cardiomyopathy (HCM). Likely pathogenic variants were found in three ARVC cases (12%) in PKP2, DSC2 or DSP, two DCM cases (20%) in MYH7, and four HCM cases (27%) in MYBPC3 (3) or MYH7 (1). Uptake of cascade screening in relatives was higher when a molecular diagnosis was made at autopsy. In three families, variants previously published as pathogenic were detected, but clinical investigation revealed no abnormalities in carrier relatives. With a conservative approach to defining pathogenicity of sequence variants incorporating family phenotype information and population genomic data, a molecular diagnosis was made in 15% of sudden arrhythmic deaths and 18% of cardiomyopathy deaths.
authors.affiliation: Department of Clinical Genetics, Ashgrove House, Aberdeen, Scotland.
authors.forename: F
authors.initials: F
authors.lastname: Cann
authors.affiliation: Pathology Department, University Medical Buildings, Aberdeen, Scotland.
authors.forename: M
authors.initials: M
authors.lastname: Corbett
authors.affiliation: North of Scotland Genetics Laboratory, Polwarth Building, Aberdeen, Scotland.
authors.forename: D
authors.initials: D
authors.lastname: O'Sullivan
authors.affiliation: North of Scotland Genetics Laboratory, Polwarth Building, Aberdeen, Scotland.
authors.forename: S
authors.initials: S
authors.lastname: Tennant
authors.affiliation: Department of Clinical Genetics, Ashgrove House, Aberdeen, Scotland.
authors.forename: H
authors.initials: H
authors.lastname: Hailey
authors.affiliation: The Forensic Medicine Unit, University Medical Buildings, Aberdeen University, Aberdeen, Scotland.
authors.forename: J H K
authors.initials: JH
authors.lastname: Grieve
authors.affiliation: Cardiology Department, Aberdeen Royal Infirmary, Aberdeen, Scotland.
authors.forename: P
authors.initials: P
authors.lastname: Broadhurst
authors.affiliation: Pathology Department, Raigmore Hospital, Inverness, Scotland.
authors.forename: R
authors.initials: R
authors.lastname: Rankin
authors.affiliation: Department of Clinical Genetics, Ashgrove House, Aberdeen, Scotland.
authors.forename: J C S
authors.initials: JC
authors.lastname: Dean
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D019571:Arrhythmogenic Right Ventricular Dysplasia / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D001344:Autopsy / Q000379:methods*; D009202:Cardiomyopathies / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D002312:Cardiomyopathy, Hypertrophic / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D053447:Channelopathies / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D016757:Death, Sudden, Cardiac / Q000209:etiology* / Q000473:pathology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D057089:Pathology, Molecular / Q000379:methods*; D010641:Phenotype; D055815:Young Adult
keywords: clinical phenotyping; genetic testing; molecular autopsy; sudden death