Author:
Makita Naomasa,Yagihara Nobue,Crotti Lia,Johnson Christopher N.,Beckmann Britt-Maria,Roh Michelle S.,Shigemizu Daichi,Lichtner Peter,Ishikawa Taisuke,Aiba Takeshi,Homfray Tessa,Behr Elijah R.,Klug Didier,Denjoy Isabelle,Mastantuono Elisa,Theisen Daniel,Tsunoda Tatsuhiko,Satake Wataru,Toda Tatsushi,Nakagawa Hidewaki,Tsuji Yukiomi,Tsuchiya Takeshi,Yamamoto Hirokazu,Miyamoto Yoshihiro,Endo Naoto,Kimura Akinori,Ozaki Kouichi,Motomura Hideki,Suda Kenji,Tanaka Toshihiro,Schwartz Peter J.,Meitinger Thomas,Kääb Stefan,Guicheney Pascale,Shimizu Wataru,Bhuiyan Zahurul A.,Watanabe Hiroshi,Chazin Walter J.,George Alfred L.
Abstract
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 cardiac death in young adults and children. Recently, mutations in calmodulin (
CALM1
,
CALM2
) have been associated with severe forms of LQTS and CPVT, with life-threatening arrhythmias occurring very early in life. Additional mutation-positive cases are needed to discern genotype–phenotype correlations associated with calmodulin mutations.
Methods and Results—
We used conventional and next-generation sequencing approaches, including exome analysis, in genotype-negative LQTS probands. We identified 5 novel de novo missense mutations in
CALM2
in 3 subjects with LQTS (p.N98S, p.N98I, p.D134H) and 2 subjects with clinical features of both LQTS and CPVT (p.D132E, p.Q136P). Age of onset of major symptoms (syncope or cardiac arrest) ranged from 1 to 9 years. Three of 5 probands had cardiac arrest and 1 of these subjects did not survive. The clinical severity among subjects in this series was generally less than that originally reported for
CALM1
and
CALM2
associated with recurrent cardiac arrest during infancy. Four of 5 probands responded to β-blocker therapy, whereas 1 subject with mutation p.Q136P died suddenly during exertion despite this treatment. Mutations affect conserved residues located within Ca
2+
-binding loops III (p.N98S, p.N98I) or IV (p.D132E, p.D134H, p.Q136P) and caused reduced Ca
2+
-binding affinity.
Conclusions—
CALM2
mutations can be associated with LQTS and with overlapping features of LQTS and CPVT.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Genetics (clinical),Cardiology and Cardiovascular Medicine,Genetics