%0 Journal Article
%A Wren, Lisa M
%A Jiménez-Jáimez, Juan
%A Al-Ghamdi, Saleh
%A Al-Aama, Jumana Y
%A Bdeir, Amnah
%A Al-Hassnan, Zuhair N
%A Kuan, Jyn L
%A Foo, Roger Y
%A Potet, Franck
%A Johnson, Christopher N
%A Aziz, Miriam C
%A Carvill, Gemma L
%A Kaski, Juan-Pablo
%A Crotti, Lia
%A Perin, Francesca
%A Monserrat, Lorenzo
%A Burridge, Paul W
%A Schwartz, Peter J
%A Chazin, Walter J
%A Bhuiyan, Zahurul A
%A George, Alfred L
%T Genetic Mosaicism in Calmodulinopathy.
%D 2019
%U http://hdl.handle.net/10668/14447
%X 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.
%K arrhythmia
%K calmodulin
%K genotype
%K long QT syndrome
%K mosaicism
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