Infanticide vs. inherited cardiac arrhythmias

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 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.

Proactive Variant Effect Mapping to Accelerate Genetic Diagnosis for Pediatric Cardiac Arrest

“…A recent striking impact of genetic diagnosis in casting doubt on an infanticide conviction is just one example of this, where the map we use here predicts a high likilhood of pathogenicity for a CALM2 VUS found in the associated cardiac arrests (c.340G>A, p.Gly114Arg). 11,12 As each of the variants discussed here was newly described, there were no functional or population data available except for the variant effect map. Without the map, the laboratory reclassification of the variant from Case 2 was fully dependent on parental sequencing: these data are costly, time intensive, and not always available clinically.…”

The Genetics and Epigenetics of Ventricular Arrhythmias in Patients Without Structural Heart Disease

“…On the other hand, the binding of calmodulin to RyR2 can inhibit the release of calcium from SR during diastole. Mutations associated with CPVT mainly lead to dysregulation of RyR2 calcium release ( 70 , 125 ).…”

“…Idiopathic ventricular fibrillation is an exclusive disease that requires excluding the presence of the ventricular fibrillation substrate and specific diseases, including structural heart disease and primary arrhythmia syndrome ( 131 ). At present, most genes related to idiopathic ventricular fibrillation overlap with the pathogenic genes of hereditary ventricular arrhythmias, such as CALM1~3, RYR2, TRDN, CACNA1C, SCN5A, KCNE5 ( 50 , 125 , 132 – 137 ). However, there are also specific causative genes in the idiopathic ventricular fibrillation ( 138 ).…”

Molecular Autopsy of Sudden Cardiac Death in the Genomics Era

“…"Molecular autopsy" refers to the processes of post-mortem genetic testing on DNA extracted from blood or tissue collected at autopsy to detect a genetic cause responsible for a SUD. The identification of a potentially pathogenic mutation prompts the screening of surviving relatives, with profound implications for their future clinical management [12]. Moreover, the demonstration of a pathophysiological substrate likely responsible for an otherwise SUD represents an invaluable element for medico-legal inquiries.…”