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

10 Scopus citations


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 (US)
Article numbere002581
Pages (from-to)375-385
Number of pages11
JournalCirculation: Genomic and Precision Medicine
Issue number9
StatePublished - Sep 1 2019


  • arrhythmia
  • calmodulin
  • genotype
  • long QT syndrome
  • mosaicism

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)


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