Publication: Genetic Mosaicism in Calmodulinopathy.
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Date
2019-08-27
Authors
Wren, Lisa M
Jiménez-Jáimez, Juan
Al-Ghamdi, Saleh
Al-Aama, Jumana Y
Bdeir, Amnah
Al-Hassnan, Zuhair N
Kuan, Jyn L
Foo, Roger Y
Potet, Franck
Johnson, Christopher N
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Abstract
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. CaM mutations were identified in 4 independent cases by DNA sequencing. Biochemical and electrophysiological studies were performed to determine functional consequences of each mutation. 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 Ca2+ 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 Ca2+-dependent inactivation of L-type Ca2+ channels and prolonged action potential duration. We report 2 families with somatic mosaicism associated with arrhythmogenic calmodulinopathy, and demonstrate dysregulation of L-type Ca2+ 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.
Description
MeSH Terms
Arrhythmias, Cardiac
Base Sequence
Calcium
Calmodulin
Child, Preschool
Electrophysiology
Female
Genetic Predisposition to Disease
Humans
Infant
Infant, Newborn
Male
Mosaicism
Mutation, Missense
Pedigree
Base Sequence
Calcium
Calmodulin
Child, Preschool
Electrophysiology
Female
Genetic Predisposition to Disease
Humans
Infant
Infant, Newborn
Male
Mosaicism
Mutation, Missense
Pedigree
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CIE Terms
Keywords
arrhythmia, calmodulin, genotype, long QT syndrome, mosaicism