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Phenotype‐driven molecular autopsy for sudden cardiac death
Author(s) -
Cann F.,
Corbett M.,
O'Sullivan D.,
Tennant S.,
Hailey H.,
Grieve J.H.K.,
Broadhurst P.,
Rankin R.,
Dean J.C.S.
Publication year - 2017
Publication title -
clinical genetics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.543
H-Index - 102
eISSN - 1399-0004
pISSN - 0009-9163
DOI - 10.1111/cge.12778
Subject(s) - myh7 , sudden cardiac death , autopsy , sudden death , medicine , hypertrophic cardiomyopathy , cardiomyopathy , channelopathy , cardiology , dilated cardiomyopathy , population , genetics , heart failure , biology , gene , environmental health , gene isoform
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.