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.
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06 November 2019
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Acknowledgements
This study was funded in part by Cardiac Risk in the Young (ERB, HR, MP, SS, MS, GM and SP); the British Heart Foundation (ERB, HR and SC) including BHF Clinical Research Training Fellowship FS/11/71/28918: Future diagnostic role and novel genetic loci in SADS; The Robert Lancaster Memorial Fund sponsored by McColl’s RG Ltd (ERB, YW and CM); NMRC Singapore (SC); Leducq Foundation (SC); NIHR Royal Brompton Cardiovascular BRU (support to JSW, RG, SAC and JAT); MRC UK (SC, JSW); Tanoto Foundation (SC); SingHealth/Duke-NUS Precision Medicine Institute (PRISM) (SC); Cure Kids (New Zealand) (JRS, JC and DRL); Wellcome Trust (JSW) and the Dutch Heart Foundation CVON-PREDICT project (CVON2012-10) (NL, EML, AAMW and CRB). All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
Members of the European Reference Network for rare and low prevalence diseases of the heart, Guard-Heart
Najim Lahrouchi, Elisabeth M. Lodder, Stathis Papatheodorou, Chris Miles, Michael Papadakis, Della Cole, Jacob Tfelt-Hansen, Christian van der Werf, Yanushi D. Wijeyeratne, Janice Till, Sanjay Sharma, Arthur A.M. Wilde, Mary N. Sheppard, Connie R. Bezzina, Elijah R. Behr.
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AAMW has undertaken consulting for Sorin in the past. ERB has received unrestricted research funds from Biotronik and St Jude Medical. The remaining authors declare that they have no conflict of interest.
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Lahrouchi, N., Raju, H., Lodder, E.M. et al. The yield of postmortem genetic testing in sudden death cases with structural findings at autopsy. Eur J Hum Genet 28, 17–22 (2020). https://doi.org/10.1038/s41431-019-0500-8
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DOI: https://doi.org/10.1038/s41431-019-0500-8
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