Infanticide vs. inherited cardiac arrhythmias

Brohus, Malene, Arsov, Todor, Wallace, David A., Jensen, Helene Halkjær, Nyegaard, Mette, Crotti, Lia, Adamski, Marcin, Zhang, Yafei, Field, Matt A., Athanasopoulo, Vicki, Baró, Isabelle, Ribeiro de Oliveira-Mendes, Bárbara B., Redon, Richard, Charpentier, Flavien, Raju, Hariharan, DiSilvestre, Deborah, Wei, Jinhong, Wang, Ruiwu, Rafehi, Haloom, Kaspi, Antony, Bahlo, Melanie, Dick, Ivy E., Chen, Sui Rong Wayne, Cook, Matthew C., Vinuesa, Carola G., Overgaard, Michael Toft, and Schwartz, Peter J. (2021) Infanticide vs. inherited cardiac arrhythmias. Europace. (In Press)

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Abstract

Aims: In 2003, an Australian woman was convicted by a jury of smothering and killing her four children over a 10-year period. Each child died suddenly and unexpectedly during a sleep period, at ages ranging from 19 days to 18 months. In 2019 we were asked to investigate if a genetic cause could explain the children’s deaths as part of an inquiry into the mother’s convictions.

Methods and results: Whole genomes or exomes of the mother and her four children were sequenced. Functional analysis of a novel CALM2 variant was performed by measuring Ca2+-binding affinity, interaction with calcium channels and channel function. We found two children had a novel calmodulin variant (CALM2 G114R) that was inherited maternally. Three genes (CALM1-3) encode identical calmodulin proteins. A variant in the corresponding residue of CALM3 (G114W) was recently reported in a child who died suddenly at age 4 and a sibling who suffered a cardiac arrest at age 5. We show that CALM2 G114R impairs calmodulin's ability to bind calcium and regulate two pivotal calcium channels (CaV1.2 and RyR2) involved in cardiac excitation contraction coupling. The deleterious effects of G114R are similar to those produced by G114W and N98S, which are considered arrhythmogenic and cause sudden cardiac death in children.

Conclusion: A novel functional calmodulin variant (G114R) predicted to cause idiopathic ventricular fibrillation, catecholaminergic polymorphic ventricular tachycardia, or mild long QT syndrome was present in two children. A fatal arrhythmic event may have been triggered by their intercurrent infections. Thus, calmodulinopathy emerges as a reasonable explanation for a natural cause of their deaths.

Item ID: 66020
Item Type: Article (Research - C1)
ISSN: 1532-2092
Keywords: BSN; CALM2; Calmodulinopathy; Infanticide; Sudden unexpected death
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Copyright Information: © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
Funders: National Health and Medical Research Council of Australia (NHMRC) Centres of Research Excellence (CRE)., Lundbeck Foundation (LF), Canadian Institutes of Health Research (CIHR), Heart and Stroke Foundation of Canada, Leducq Foundation for Cardiovascular Research
Projects and Grants: NHMRC CRE
Date Deposited: 17 Feb 2021 04:13
FoR Codes: 31 BIOLOGICAL SCIENCES > 3102 Bioinformatics and computational biology > 310204 Genomics and transcriptomics @ 100%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 100%
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