Wren, LM; Jiménez-Jáimez, J; Al-Ghamdi, S; Al-Aama, JY; Bdeir, A; Al-Hassnan, ZN; Kuan, JL; ... George, AL; + view all Wren, LM; Jiménez-Jáimez, J; Al-Ghamdi, S; Al-Aama, JY; Bdeir, A; Al-Hassnan, ZN; Kuan, JL; Foo, RY; Potet, F; Johnson, CN; Aziz, MC; Carvill, GL; Kaski, J-P; Crotti, L; Perin, F; Monserrat, L; Burridge, PW; Schwartz, PJ; Chazin, WJ; Bhuiyan, ZA; George, AL; - view fewer (2019) Genetic Mosaicism in Calmodulinopathy. Circulation: Genomic and Precision Medicine , 12 (9) pp. 375-385. 10.1161/CIRCGEN.119.002581.

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Abstract

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.

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