Novel Calmodulin Mutations Associated With Congenital Arrhythmia Susceptibility

• DOI: 10.1161/circgenetics.113.000459
• Publication Date: 2014-06-11T02:15:54Z
• Authors: Naomasa Makita; Nobue Yagihara; Lia Crotti; Christopher N. Jo...; Britt-Maria Beckmann; Michelle S. Roh; Daichi Shigemizu; Peter Lichtner; Taisuke Ishikawa; Takeshi Aiba; Tessa Homfray; Elijah R. Behr; Didier Klug; Isabelle Denjoy; Elisa Mastantuono; Daniel Theisen; Tatsuhiko Tsunoda; Wataru Satake; Tatsushi Toda; Hidewaki Nakagawa; Yukiomi Tsuji; Takeshi Tsuchiya; Hirokazu Yamamoto; Yoshihiro Miyamoto; Naoto Endo; Akinori Kimura; Kouichi Ozaki; Hideki Motomura; Kenji Suda; Toshihiro Tanaka; Peter J. Schwartz; Thomas Meitinger; Stefan Kääb; Pascale Guicheney; Wataru Shimizu; Zahurul A. Bhuiyan; Hiroshi Watanabe; Walter J. Chazin; Alfred L. George
• Keywords: Proband; Sudden Death

Background— Genetic predisposition to life-threatening cardiac arrhythmias such as congenital long-QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) represent treatable causes of sudden death in young adults children. Recently, mutations calmodulin ( CALM1 , CALM2 ) have been associated with severe forms LQTS CPVT, occurring very early life. Additional mutation-positive cases are needed discern genotype–phenotype correlations mutations. Methods Results— We used conventional next-generation sequencing approaches, including exome analysis, genotype-negative probands. identified 5 novel de novo missense 3 subjects (p.N98S, p.N98I, p.D134H) 2 clinical features both CPVT (p.D132E, p.Q136P). Age onset major symptoms (syncope or arrest) ranged from 1 9 years. Three probands had arrest these did not survive. The severity among this series was generally less than that originally reported for recurrent during infancy. Four responded β-blocker therapy, whereas subject mutation p.Q136P died suddenly exertion despite treatment. Mutations affect conserved residues located within Ca 2+ -binding loops III p.N98I) IV p.D134H, p.Q136P) caused reduced affinity. Conclusions— can be overlapping CPVT.