Genetic Mosaicism in Calmodulinopathy

Lisa M Wren, Juan Jiménez-Jáimez, Saleh Al-Ghamdi, Jumana Y Al-Aama, Amnah Bdeir, Zuhair N Al-Hassnan, Jyn L Kuan, Roger Y Foo, Franck Potet, Christopher N Johnson, Miriam C Aziz, Gemma L Carvill, Juan-Pablo Kaski, Lia Crotti, Francesca Perin, Lorenzo Monserrat, Paul W Burridge, Peter J Schwartz, Walter J Chazin, Zahurul A BhuiyanAlfred L George

Research output: Contribution to journalArticlepeer-review


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 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.

CONCLUSIONS: 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.

Original languageEnglish
Pages (from-to)375-385
Number of pages11
JournalCirculation. Genomic and precision medicine
Issue number9
Publication statusPublished - Sep 2019


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