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Infanticide vs. inherited cardiac arrhythmias

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avisTidsskriftartikelForskningpeer review

DOI

  • Malene Brohus, Aalborg Universitet
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  • Todor Arsov, Australian Research School of Chemistry, Australian National University, Canberra, Columbia University Irving Medical Center
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  • David A Wallace, Australian Research School of Chemistry, Australian National University, Canberra
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  • Helene Halkjær Jensen, Aalborg Universitet
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  • Mette Nyegaard
  • Lia Crotti, Center for Cardiac Arrhythmias of Genetic Origin, IRCCS, University of Milano Bicocca
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  • Marcin Adamski, The Australian National University
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  • Yafei Zhang, Australian Research School of Chemistry, Australian National University, Canberra
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  • Matt A Field, Australian Research School of Chemistry, Australian National University, Canberra, James Cook University Queensland
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  • Vicki Athanasopoulos, Australian Research School of Chemistry, Australian National University, Canberra
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  • Isabelle Baró, CRCINA, Inserm UMR892 / CNRS UMR6299, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, Université de Nantes, Nantes, France.
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  • Bárbara B Ribeiro de Oliveira-Mendes, CRCINA, Inserm UMR892 / CNRS UMR6299, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, Université de Nantes, Nantes, France.
  • ,
  • Richard Redon, CRCINA, Inserm UMR892 / CNRS UMR6299, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, Université de Nantes, Nantes, France.
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  • Flavien Charpentier, CRCINA, Inserm UMR892 / CNRS UMR6299, Centre de Recherche en Cancérologie et Immunologie Nantes-Angers, Université de Nantes, Nantes, France.
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  • Hariharan Raju, Macquarie Univ, Macquarie University, Dept Biol Sci
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  • Deborah DiSilvestre, University of Maryland School of Medicine, University of Maryland Hospital, Baltimore, Maryland.
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  • Jinhong Wei, University of Calgary, Calgary, Canada.
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  • Ruiwu Wang, University of Calgary, Calgary, Canada.
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  • Haloom Rafehi, The Walter and Eliza Hall Institute of Medical Research, University of Melbourne
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  • Antony Kaspi, The Walter and Eliza Hall Institute of Medical Research, University of Melbourne
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  • Melanie Bahlo, The Walter and Eliza Hall Institute of Medical Research, University of Melbourne
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  • Ivy E Dick, University of Maryland School of Medicine, University of Maryland Hospital, Baltimore, Maryland.
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  • Sui Rong Wayne Chen, University of Calgary, Calgary, Canada.
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  • Matthew C Cook, Australian Research School of Chemistry, Australian National University, Canberra
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  • Carola G Vinuesa, Australian Research School of Chemistry, Australian National University, Canberra
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  • Michael Toft Overgaard, Aalborg Universitet
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  • Peter J Schwartz, Center for Cardiac Arrhythmias of Genetic Origin

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 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.

OriginalsprogEngelsk
TidsskriftEuropace
Vol/bind23
Nummer3
Sider (fra-til)441-450
Antal sider10
ISSN1099-5129
DOI
StatusUdgivet - mar. 2021

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