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Eur J Hum Genet. 2019 Sep 18. doi: 10.1038/s41431-019-0500-8. [Epub ahead of print]

The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy.

Author information

1
Amsterdam UMC, University of Amsterdam, Heart Center; Department of Clinical and Experimental Cardiology, Amsterdam Cardiovascular Sciences, Meibergdreef 9, Amsterdam, The Netherlands.
2
Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK.
3
Cardiology Clinical Academic Group, St George's University Hospitals NHS Foundation Trust, London, UK.
4
National Heart and Lung Institute, Imperial College London, Sydney Street, London, UK.
5
Royal Brompton Hospital, London, UK.
6
Cardiovascular Genetics Center, Montreal Heart Institute and Faculty of Medicine, Université de Montréal, Montreal, Canada.
7
Cardiac Inherited Disease Group New Zealand, Green Lane Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand.
8
The University of Auckland, Department of Paediatrics Child and Youth Health, Auckland, New Zealand.
9
National Heart Centre Singapore, 5 Hospital Drive, Singapore, 169609, Singapore.
10
Department of Cardiology, Rigshospitalet, Copenhagen, Denmark.
11
Sheffield Children's NHS Foundation Trust, Sheffield, UK.
12
Duke-NUS, 8 College Road, Singapore, 169857, Singapore.
13
Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, UK. ebehr@sgul.ac.uk.
14
Cardiology Clinical Academic Group, St George's University Hospitals NHS Foundation Trust, London, UK. ebehr@sgul.ac.uk.

Abstract

Sudden cardiac death (SCD) is often associated with structural abnormalities of the heart during autopsy. This study sought to compare the diagnostic yield of postmortem genetic testing in (1) cases with structural findings of uncertain significance at autopsy to (2) cases with autopsy findings diagnostic of cardiomyopathy. We evaluated 57 SCD cases with structural findings at cardiac autopsy. Next-generation sequencing using a panel of 77 primary electrical disorder and cardiomyopathy genes was performed. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. In 29 cases (51%) autopsy findings of uncertain significance were identified whereas in 28 cases (49%) a diagnosis of cardiomyopathy was established. We identified a pathogenic or likely pathogenic variant in 10 cases (18%); in 1 (3%) case with non-specific autopsy findings compared with 9 (32%) cases with autopsy findings diagnostic of cardiomyopathy (p = 0.0054). The yield of genetic testing in SCD cases with autopsy findings consistent with cardiomyopathy is comparable with the yield in cardiomyopathy patients that are alive. Genetic testing in cases with findings of uncertain significance offers lower clinical utility than in cardiomyopathy, with lower yields than detected previously. This highlights the need for stringent evaluation of variant pathogenicity.

PMID:
31534214
DOI:
10.1038/s41431-019-0500-8

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