Phenotype-driven molecular autopsy for sudden cardiac death

F Cann, M Corbett, D O'Sullivan, S. Tennant, H. Hailey, J H K Grieve, P Broadhurst, R Rankin, J C S Dean

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14 Citations (Scopus)

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. 46 cases aged 1-40 years had normal hearts and suspected arrhythmic death. 7 (15%) had likely pathogenic variants in ion channelopathy genes (KCNQ1 (1), KCNH2 (4), SCN5A (1), RyR2(1)). 50 cases aged between 2 and 67 had a cardiomyopathy. 25 had Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC), 10 Dilated Cardiomyopathy (DCM) and 15 Hypertrophic Cardiomyopathy (HCM). Likely pathogenic variants were found in 3 ARVC cases (12%) in PKP2, DSC2 or DSP, 2 DCM cases (20%) in MYH7, and 4 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 3 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.
Original languageEnglish
Pages (from-to)22-29
Number of pages8
JournalClinical Genetics
Volume91
Issue number1
Early online date11 May 2016
DOIs
Publication statusPublished - 1 Jan 2017

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Keywords

  • clinical phenotyping
  • genetic testing
  • molecular autopsy
  • sudden death

Cite this

Cann, F., Corbett, M., O'Sullivan, D., Tennant, S., Hailey, H., Grieve, J. H. K., ... Dean, J. C. S. (2017). Phenotype-driven molecular autopsy for sudden cardiac death. Clinical Genetics, 91(1), 22-29. https://doi.org/10.1111/cge.12778