start-ver=1.4
cd-journal=joma
no-vol=89
cd-vols=
no-issue=6
article-no=
start-page=835
end-page=844
dt-received=
dt-revised=
dt-accepted=
dt-pub-year=2025
dt-pub=20250523
dt-online=
en-article=
kn-article=
en-subject=
kn-subject=
en-title=
kn-title=Clinical Impact of Genetic Testing for Long QT Syndrome ― Evidence From a Nationwide LQTS Registry in Japan ―
en-subtitle=
kn-subtitle=
en-abstract=
kn-abstract=Background: Genetic testing for long QT syndrome (LQTS) is useful for diagnosis, risk stratification, and therapeutic strategies. This study investigated the clinical impact of genetic testing for LQTS patients.
Methods and Results: Total 3,851 patients (proband: 2,316 [60%]; female: 2,283 [59%]; median age: 14 years [interquartile range 9–36 years]) diagnosed with LQTS (LQTS score ≥3.5, QTc ≥500 ms, pathogenic variants in LQTS-associated genes, or unexplored syncope with QTc 480–499 ms) were enrolled in this study. Of these patients, 1,146 (29.8%) experienced syncope and 322 (8.5%) experienced ventricular fibrillation (VF) or cardiopulmonary arrest (CPA) at ≤70 years of age. Genetic testing using a next-generation sequencing panel and/or Sanger sequencing was performed for 3,770 (98%) patients, genotype was then identified in the following LQTS-associated genes: KCNQ1 (45%), KCNH2 (34%), SCN5A (8%), KCNE1 (0.1%), KCNE2 (0.03%), KCNJ2 (2.7%), CACNA1C (1.2%), and CALM1,2 (0.3%). Forty-seven (1.2%) patients had double or compound heterozygous variants in LQTS-associated genes, whereas the genotype remained unknown in 220 (5.8%) patients. When comparing phenotype with genotype, QTc was significantly longer in CALM1,2 patients than in others except for CACNA1C, whereas QTc was almost normal in KCNJ2 patients. The incidence of the first cardiac event (syncope, VF/CPA) differed among the genotypes, and prognosis was significantly worse for CALM1,2 patients.
Conclusions: Comprehensive genetic testing, including non-major LQTS genes, is important for diagnosis and risk stratification of LQTS.
en-copyright=
kn-copyright=
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ORCID=
affil-num=1
en-affil=Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=2
en-affil=Medical Genome Center, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=3
en-affil=Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=4
en-affil=Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=5
en-affil=Department of Pediatric Cardiology, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=6
en-affil=Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=7
en-affil=Medical Genome Center, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=8
en-affil=Division of Counseling for Medical Genetics, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=9
en-affil=Department of Pediatric Cardiology, Saitama Medical University International Medical Center
kn-affil=
affil-num=10
en-affil=Department of Pediatric Cardiology, Saitama Medical University International Medical Center
kn-affil=
affil-num=11
en-affil=Department of Child Health, Institution of Medicine, University of Tsukuba
kn-affil=
affil-num=12
en-affil=Department of Pediatrics, National Hospital Organization Kagoshima Medical Center
kn-affil=
affil-num=13
en-affil=Department of Cardiovascular Medicine, Shiga University of Medical Science
kn-affil=
affil-num=14
en-affil=Department of Cardiovascular Medicine, Shiga University of Medical Science
kn-affil=
affil-num=15
en-affil=Department of Cardiology, Kyoto University
kn-affil=
affil-num=16
en-affil=Department of Cardiovascular Medicine, Kanazawa University Graduate School of Medical Sciences
kn-affil=
affil-num=17
en-affil=Department of Medical Education, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University Graduate School of Medical Sciences
kn-affil=
affil-num=18
en-affil=Okayama University Graduate School of Medicine
kn-affil=
affil-num=19
en-affil=Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine
kn-affil=
affil-num=20
en-affil=Department of Cardiovascular Medicine, Gunma University Graduate School of Medicine
kn-affil=
affil-num=21
en-affil=Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences
kn-affil=
affil-num=22
en-affil=Cardiovascular Biology and Medicine, Niigata University Graduate School of Medical and Dental Sciences
kn-affil=
affil-num=23
en-affil=Department of Medical Genetics, Shinshu University School of Medicine
kn-affil=
affil-num=24
en-affil=Osaka City General Hospital
kn-affil=
affil-num=25
en-affil=Hokkaido Children’s Hospital
kn-affil=
affil-num=26
en-affil=Department of Pediatrics, Teine-Keijinkai Hospital
kn-affil=
affil-num=27
en-affil=Department of Pediatrics, Yamagata University Faculty of Medicine
kn-affil=
affil-num=28
en-affil=Department of Cardiology, Nagoya University Graduate School of Medicine
kn-affil=
affil-num=29
en-affil=Department of Pediatrics, Tokushima University
kn-affil=
affil-num=30
en-affil=Fukuoka Children’s Hospital
kn-affil=
affil-num=31
en-affil=Yokohama City University
kn-affil=
affil-num=32
en-affil=Department of Preventive Medicine and Epidemiology, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=33
en-affil=Department of Genomic Medicine, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=34
en-affil=Department of Child Health, Institution of Medicine, University of Tsukuba
kn-affil=
affil-num=35
en-affil=Department of Pediatrics, National Hospital Organization Kagoshima Medical Center
kn-affil=
affil-num=36
en-affil=Department of Cardiovascular Medicine, Shiga University of Medical Science
kn-affil=
affil-num=37
en-affil=Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
affil-num=38
en-affil=Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center (NCVC)
kn-affil=
en-keyword=Arrhythmia
kn-keyword=Arrhythmia
en-keyword=Diagnosis
kn-keyword=Diagnosis
en-keyword=Genetic testing
kn-keyword=Genetic testing
en-keyword=Long QT syndrome
kn-keyword=Long QT syndrome
en-keyword=Sudden cardiac death
kn-keyword=Sudden cardiac death
END