Abstract Background Cardiac calmodulinopathy is a life-threatening arrhythmia syndrome which presents several phenotypes of inherited primary arrhythmia syndrome (IPAS), and caused by mutations in calmodulin-encoded genes (CALM1–3). We aimed clarify the frequency and their clinical characteristics of calmodulinopathy in our IPAS cohort. Methods By using next generation sequencing, we screened arrhythmia related genes including calmodulin-encoding genes in 322 unrelated symptomatic children (0–12 years) who were suspected as IPAS; they included 40 cases with lethal arrhythmic attacks (LAE) under 6-year-old. After gene screening, we investigated their physiological and clinical characteristics about mutation carriers. Results Among 322 children, we identified 6 mutations of calmodulin-encoded genes in 9 probands (2.8%); one CALM1 in 2 probands (N98S), and 5 CALM2 in 7 probands (E46K, D96V, D96G, N98S, E141K). Their clinical diagnoses were long QT syndrome (LQTS, n=4), catecholaminergic polymorphic ventricular tachycardia (CPVT, n=3) and both (n=2). Their age of diagnosis ranges at 0–9 with the median of 5 years. There were three major clinical phenotypes; 1) CALM2-D96V, and E141K: two infants with advanced atrio-ventricular block, significant QTc prolongation, severe heart failure from their fetal period – both of them deceased within 1.5-year-old. Their clinical phenotypes resembled classical Timothy syndrome caused by CACNA1C mutations. 2) CALM1-N98S (n=2), CALM2-N98S (n=2), and CALM2-D96G: four preschoolers with LAEs and one syncope: all of them were 3–5 years old. In addition, a T wave morphology of CALM2-D96G carrier was very similar to LQT1. 3) CALM2-E46K (n=2): two were first diagnosed with neurological and developmental disorders, and showed phenotype of CPVT: their cardiac phenotypes were milder compared with that of 1) or 2). Overall, these phenotypes seemed to be mutation specific (indicated in figure). Their cardiac features were severer, and the onset of LAEs was earlier compared with other genotypes of LQTS/CPVT. As the treatment, β-blocker was effective for control of LAEs. Conclusion Cardiac calmodulinopathy presented serious and potentially lethal phenotypes in fetus or infancy. To prevent cardiac death in them, we must correctly diagnose and start the treatment as earlier as possible. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): MEXT KAKENHI from the Ministry of Education, Culture, Sports, Science, and Technology of Japan