Key result
Novel CaM mutations impaired Ca2+ binding and prolonged action potential duration, with somatic mosaicism identified in asymptomatic parents of affected probands.
Why the study?
Calmodulin mutations are linked to congenital arrhythmia susceptibility and are usually de novo; this study sought to expand the genotype-phenotype spectrum with 2 novel mutations and evaluate mosaicism in 2 affected families.
Case Report (n=4)
Demonstrates that somatic mosaicism in asymptomatic parents can cause arrhythmogenic calmodulinopathy in offspring, highlighting the need to suspect parental mosaicism in unexplained fetal arrhythmia or demise.
May support parental mosaicism testing in unexplained fetal arrhythmias; leaves open broader screening recommendations.
Background: CaM (calmodulin) mutations are associated with congenital arrhythmia susceptibility (calmodulinopathy) and are most often de novo. In this report, we sought to broaden the genotype-phenotype spectrum of calmodulinopathies with 2 novel calmodulin mutations and to investigate mosaicism in 2 affected families. Methods: CaM mutations were identified in 4 independent cases by DNA sequencing. Biochemical and electrophysiological studies were performed to determine functional consequences of each mutation. Results: Genetic studies identified 2 novel CaM variants ( CALM3 -E141K in 2 cases; CALM1 -E141V) and one previously reported CaM pathogenic variant ( CALM3 -D130G) among 4 probands with shared clinical features of prolonged QTc interval (range 505–725 ms) and documented ventricular arrhythmia. A fatal outcome occurred for 2 of the cases. The parents of all probands were asymptomatic with normal QTc duration. However, 2 of the families had multiple affected offspring or multiple occurrences of intrauterine fetal demise. The mother from the family with recurrent intrauterine fetal demise exhibited the CALM3 -E141K mutant allele in 25% of next-generation sequencing reads indicating somatic mosaicism, whereas CALM3 -D130G was present in 6% of captured molecules of the paternal DNA sample, also indicating mosaicism. Two novel mutations (E141K and E141V) impaired Ca 2+ binding affinity to the C-domain of CaM. Human-induced pluripotent stem cell-derived cardiomyocytes overexpressing mutant or wild-type CaM showed that both mutants impaired Ca 2+ -dependent inactivation of L-type Ca 2+ channels and prolonged action potential duration. Conclusions: We report 2 families with somatic mosaicism associated with arrhythmogenic calmodulinopathy, and demonstrate dysregulation of L-type Ca 2+ channels by 2 novel CaM mutations affecting the same residue. Parental mosaicism should be suspected in families with unexplained fetal arrhythmia or fetal demise combined with a documented CaM mutation.
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Wren et al. (2019) conducted a case report in Calmodulinopathy (n=4). CaM mutations (CALM3-E141K, CALM1-E141V, CALM3-D130G) vs. Wild-type CaM (in vitro) was evaluated on Identification of CaM mutations, somatic mosaicism, and functional electrophysiological consequences. Novel CaM mutations impaired Ca2+ binding and prolonged action potential duration, with somatic mosaicism identified in asymptomatic parents of affected probands.
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