Calmodulinopathy in Japanese Children　― Their Cardiac Phenotypes Are Severe and Show Early Onset in Fetal Life and Infancy

• Published in: Circulation Journal Vol. 87; no. 12; pp. 1828 - 1835
• Main Authors: Kato, Koichi, Horie, Minoru, Sakazaki, Hisanori, Ueno, Michihiko, Toda, Takako, Aoki, Hisaaki, Yoshida, Yoko, Momoi, Nobuo, Makiyama, Takeru, Nakagawa, Yoshihisa, Fujita, Shuhei, Ohno, Seiko, Izumi, Gaku, Muneuchi, Jun, Fukuyama, Megumi
• Format: Journal Article
• Language: English
• Published: Japan The Japanese Circulation Society 24.11.2023
• Subjects: Arrhythmias, Cardiac - genetics; Calmodulin - genetics; Calmodulin - metabolism; Calmodulinopathy; Catecholaminergic polymorphic ventricular tachycardia; Child; Child, Preschool; Death, Sudden, Cardiac - etiology; East Asian People; Genetic testing; Humans; Infant; Infant, Newborn; Long QT syndrome; Long QT Syndrome - diagnosis; Long QT Syndrome - genetics; Neurological disorders; Phenotype; Tachycardia, Ventricular - diagnosis; Tachycardia, Ventricular - genetics; Long QT syndrome; Catecholaminergic polymorphic ventricular tachycardia; Genetic testing; Neurological disorders; Calmodulinopathy
• ISSN: 1346-9843; 1347-4820; 1347-4820
• DOI: 10.1253/circj.CJ-23-0195

Background: Cardiac calmodulinopathy, characterized by a life-threatening arrhythmia and sudden death in the young, is extremely rare and caused by genes encoding calmodulin, namely calmodulin 1 (CALM1), CALM2, and CALM3.Methods and Results: We screened 195 symptomatic children (age 0–12 years) who were suspected of inherited arrhythmias for 48 candidate genes, using a next-generation sequencer. Ten probands were identified as carrying variants in any of CALM1–3 (5%; median age 5 years), who were initially diagnosed with long QT syndrome (LQTS; n=5), catecholaminergic polymorphic ventricular tachycardia (CPVT; n=3), and overlap syndrome (n=2). Two probands harbored a CALM1 variant and 8 probands harbored 6 CALM2 variants. There were 4 clinical phenotypes: (1) documented lethal arrhythmic events (LAEs): 4 carriers of N98S in CALM1 or CALM2; (2) suspected LAEs: CALM2 p.D96G and D132G carriers experienced syncope and transient cardiopulmonary arrest under emotional stimulation; (3) critical cardiac complication: CALM2 p.D96V and p.E141K carriers showed severe cardiac dysfunction with QTc prolongation; and (4) neurological and developmental disorders: 2 carriers of CALM2 p.E46K showed cardiac phenotypes of CPVT. Beta-blocker therapy was effective in all cases except cardiac dysfunction, especially in combination with flecainide (CPVT-like phenotype) and mexiletine (LQTS-like).Conclusions: Calmodulinopathy patients presented severe cardiac features, and their onset of LAEs was earlier in life, requiring diagnosis and treatment at the earliest age possible.