Abstract
We aimed to investigate the pathogenicity of cardiac ion channel variants previously associated with SIDS. We reviewed SIDS-associated variants previously reported in databases and the literature in three large population-based cohorts; The ExAC database, the Inter99 study, and the UK Biobank (UKBB). Variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Of the 92 SIDS-associated variants, 59 (64%) were present in ExAC, 18 (20%) in Inter99, and 24 (26%) in UKBB. Using the Inter99 cohort, we found no difference in J-point amplitude and QTc-interval between carriers and non-carriers for 14/18 variants. There was no difference in the risk of syncope (P = 0.32), malignant ventricular arrhythmia (P = 0.96), and all-cause mortality (P = 0.59) between carriers and non-carriers. The ACMG guidelines reclassified 75% of all variants as variant-of-uncertain significance, likely benign, and benign. We identified ~2/3 of variants previously associated with SIDS and found no significant associations with electrocardiographic traits, syncope, malignant ventricular arrhythmia, or all-cause mortality. These data indicate that many of these variants are not highly penetrant, monogenic causes of SIDS and underline the importance of frequent reappraisal of genetic variants to avoid future misdiagnosis.
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Acknowledgements
We wish to thank the Exome Aggregation Consortium (ExAC) and the contributing projects in creating this resource for biomedical research. ExAC was funded by grants from the National Institutes of Health’s National Institute of General Medical Sciences (R01 GM104371) and National Institute of Diabetes and Digestive and Kidney Diseases R01 (U54 DK105566).
Funding
The study was supported by The John and Birthe Meyer foundation, The Foundation of 17-12-1981, The Research Foundation of the Heart Center Rigshospitalet, The Danish Heart Foundation (grant no. 11-04-R84-A3401-22654), The Danish National Research Foundation Center for Cardiac Arrhythmia, The Arvid Nilsson Foundation, The Aase and Ejnar Danielsen Foundation, Fondsbørsvekselerer Henry Hansen og Hustru Karla Hansen født Westergaards Legat, Direktør Ib Henriksens Fond, and the Hallas Møller Grant of the Novo Nordisk Foundation.
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Paludan-Müller, C., Ghouse, J., Vad, O.B. et al. Reappraisal of variants previously linked with sudden infant death syndrome: results from three population-based cohorts. Eur J Hum Genet 27, 1427–1435 (2019). https://doi.org/10.1038/s41431-019-0416-3
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DOI: https://doi.org/10.1038/s41431-019-0416-3
