A de novo mutation in Caveolin-3 gene may confer genetic susceptibility to Long QT syndrome

2011 ◽  
Vol 3 (1) ◽  
pp. e287-e288
Author(s):  
F. Alessandrini ◽  
A.A. Nasti ◽  
M. Pesaresi ◽  
V. Lariccia ◽  
A. Tagliabracci ◽  
...  
Keyword(s):  
Genetic Susceptibility ◽  
Long Qt Syndrome ◽  
De Novo ◽  
De Novo Mutation ◽  
Long Qt ◽  
Qt Syndrome

Neonatal Long QT Syndrome Due to a De Novo Dominant Negative hERG Mutation

2007 ◽  
Vol 16 (4) ◽  
pp. 416-412 ◽  
Author(s):  
Theresa A. Beery ◽  
Kerry A. Shooner ◽  
D. Woodrow Benson
Keyword(s):  
Long Qt Syndrome ◽  
De Novo ◽  
Sinus Bradycardia ◽  
Molecular Genetic ◽  
Ventricular Tachyarrhythmia ◽  
Dominant Negative ◽  
De Novo Mutation ◽  
Long Qt ◽  
Dominant Negative Mutation ◽  
Qt Syndrome

A 4-day-old girl with ventricular tachyarrhythmias, sinus bradycardia, and 2:1 atrioventricular block had prolongation of the QT interval. She was symptomatic with arching, gasping, and cyanosis presumably due to a life-threatening ventricular tachyarrhythmia such as torsades de pointes. Molecular genetic studies indicated a heterozygous, de novo, dominant negative mutation in hERG, a gene that encodes a protein in a potassium ion channel. The parents do not have the mutation. The patient’s clinical scenario was produced by the convergence of 3 events: a de novo mutation occurred in hERG, the mutation was dominant negative, and the action of the mutation resulted in neonatal long QT syndrome. The child was treated aggressively and is doing well at age 6 years.

scholarly journals Complex and Novel Arrhythmias Precede Stillbirth in Fetuses With De Novo Long QT Syndrome

2020 ◽  
Vol 13 (5) ◽  
Author(s):  
Sarah Strand ◽  
Janette F. Strasburger ◽  
Bettina F. Cuneo ◽  
Ronald T. Wakai
Keyword(s):  
Atrioventricular Block ◽  
Long Qt Syndrome ◽  
De Novo ◽  
Perinatal Death ◽  
Torsade De Pointes ◽  
Fetal Loss ◽  
Long Qt ◽  
Premature Ventricular Contractions ◽  
Fetal Magnetocardiography ◽  
Qt Syndrome

Background: Long QT syndrome (LQTS) is a leading cause of sudden cardiac death in early life and has been implicated in ≈10% of sudden infant deaths and unexplained stillbirths. The purpose of our study was to use fetal magnetocardiography to characterize the electrophysiology and rhythm phenotypes of fetuses with de novo and inherited LQTS variants and identify risk factors for sudden death before birth. Methods: We reviewed the fetal magnetocardiography database from the University of Wisconsin Biomagnetism Laboratory for fetuses with confirmed LQTS. We assessed waveform intervals, heart rate, and rhythm, including the signature LQTS rhythms: functional 2° atrioventricular block, T-wave alternans, and torsade de pointes (TdP). Results: Thirty-nine fetuses had pathogenic variants in LQTS genes: 27 carried the family variant, 11 had de novo variants, and 1 was indeterminate. De novo variants, especially de novo SCN5A variants, were strongly associated with a severe rhythm phenotype and perinatal death: 9 (82%) showed signature LQTS rhythms, 6 (55%) showed TdP, 5 (45%) were stillborn, and 1 (9%) died in infancy. Those that died exhibited novel fetal rhythms, including atrioventricular block with 3:1 conduction ratio, QRS alternans in 2:1 atrioventricular block, long-cycle length TdP, and slow monomorphic ventricular tachycardia. Premature ventricular contractions were also strongly associated with TdP and perinatal death. Fetuses with familial variants showed a lower incidence of signature LQTS rhythm (6/27=22%), including TdP (3/27=11%). All were live born. Conclusions: The malignancy of de novo LQTS variants was remarkably high and demonstrate that these mutations are a significant cause of stillbirth. Their ability to manifest rhythms not known to be associated with LQTS increases the difficulty of echocardiographic diagnosis and decreases the likelihood that a resultant fetal loss is attributed to LQTS. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT03047161.

scholarly journals A de novo missense mutation of human cardiac Na+ channel exhibiting novel molecular mechanisms of long QT syndrome

FEBS Letters ◽  
1998 ◽  
Vol 423 (1) ◽  
pp. 5-9 ◽  
Author(s):  
Naomasa Makita ◽  
Nobumasa Shirai ◽  
Masato Nagashima ◽  
Rumiko Matsuoka ◽  
Yoichi Yamada ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Long Qt Syndrome ◽  
Molecular Mechanisms ◽  
De Novo ◽  
Na Channel ◽  
Long Qt ◽  
Qt Syndrome

Long QT syndrome with a de novo CALM2 mutation in a 4‐year‐old boy

2019 ◽  
Vol 61 (9) ◽  
pp. 852-858 ◽  
Author(s):  
Shuhei Fujita ◽  
Ryo Nakagawa ◽  
Takeshi Futatani ◽  
Noboru Igarashi ◽  
Takamasa Fuchigami ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
De Novo ◽  
Long Qt ◽  
Qt Syndrome

A de novo missense mutation (R1623Q) of the SCN5A gene in a Japanese girl with sporadic long QT syndrome

1998 ◽  
Vol 11 (6) ◽  
pp. 481-481 ◽  
Author(s):  
Hiroyuki Yamagishi ◽  
Michiko Furutani ◽  
Mitsuhiro Kamisago ◽  
Yoshiyuki Morikawa ◽  
Yoshifumi Kojima ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Long Qt Syndrome ◽  
De Novo ◽  
Long Qt ◽  
Qt Syndrome ◽  
Scn5a Gene

Genetic susceptibility to acquired long QT syndrome: Pharmacologic challenge in first-degree relatives

Heart Rhythm ◽  
2005 ◽  
Vol 2 (2) ◽  
pp. 134-140 ◽  
Author(s):  
Prince J. Kannankeril ◽  
Dan M. Roden ◽  
Kris J. Norris ◽  
S.Patrick Whalen ◽  
Alfred L. George ◽  
...  
Keyword(s):  
Genetic Susceptibility ◽  
Long Qt Syndrome ◽  
Long Qt ◽  
First Degree Relatives ◽  
Acquired Long Qt Syndrome ◽  
Qt Syndrome

Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2-S3 inner loop ofHERG

2001 ◽  
Vol 98 (4) ◽  
pp. 348-352 ◽  
Author(s):  
Hidetada Yoshida ◽  
Minoru Horie ◽  
Hideo Otani ◽  
Tetsuya Kawashima ◽  
Yoshio Onishi ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Long Qt Syndrome ◽  
De Novo ◽  
Long Qt ◽  
Qt Syndrome

Abstract 359: Highly Malignant Perinatal Variant of Long-QT Syndrome Caused by a Profoundly Dysfunctional SCN5A Mutation Successfully Treated with Mexiletine and Propranolol

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Dao W Wang ◽  
Lia Crotti ◽  
Chiara Ferrandi ◽  
Thomas H Rhodes ◽  
Francesco Cantu ◽  
...  
Keyword(s):  
Long Qt Syndrome ◽  
Single Channel ◽  
De Novo ◽  
Polymorphic Ventricular Tachycardia ◽  
Pharmacological Properties ◽  
Patch Clamp Recording ◽  
Long Qt ◽  
Qt Syndrome ◽  
Illustrated Novel

Perinatal presentation of long-QT syndrome (LQTS) is uncommon but typically more severe and often fatal. We studied the functional and pharmacological properties of a novel SCN5A mutation associated with a highly malignant perinatal variant of LQTS successfully treated with mexiletine and propranolol. The proband was delivered by emergency C-section at 32-weeks because of fetal arrhythmia. Immediately after birth, the infant had polymorphic ventricular tachycardia and a slow sinus rate that were unresponsive to Mg and isoproterenol. Lidocaine controlled ventricular arrhythmia and allowed recognition of a prolonged QTc (520 ms). Treatment with propranolol (1 mg/kg/d) and mexiletine (11 mg/kg/d) normalized the QTc (410 ms) and suppressed ventricular ectopy. One month after discharge, the infant survived ventricular fibrillation and later developed paroxysmal atrial flutter. Genetic testing revealed a novel, de novo missense SCN5A mutation (G1631D) located immediately before the 4 th arginine residue in D4/S4. In vitro electrophysiological studies using whole-cell patch clamp recording of channels expressed in tsA201 cells revealed a profound defect in channel function characterized by ∼10-fold slowing of inactivation, increased persistent current, marked slowing of recovery from inactivation, depolarized voltage-dependence of activation and steady-state channel availability. Single channel recordings demonstrated increased frequency of late openings, increased open times and bursting. These biophysical properties were distinct from typical LQT3 mutations and represent the most severely dysfunctional SCN5A mutation ever reported. The mutant also exhibited 2-fold enhancement of tonic and use-dependent block by mexiletine as compared with wild-type channels. Unexpectedly, the mutant channel also exhibited enhanced tonic block (2.4-fold) and use-dependent block (∼5-fold) by propranolol. Our study demonstrated the molecular basis for a highly malignant perinatal variant of LQTS, illustrated novel functional and pharmacological properties of SCN5A -G1631D which caused the disorder, and illustrated an unexpected clinical benefit of propranolol in blocking mutant Na channels in this setting.

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