An NGS-based genotyping in LQTS; minor genes are no longer minor.
Adolescent
Adult
Aged
Calcium Channels, L-Type
/ genetics
Child
Child, Preschool
ERG1 Potassium Channel
/ genetics
Female
Genetic Predisposition to Disease
Genotype
High-Throughput Nucleotide Sequencing
Humans
Infant
Infant, Newborn
KCNQ1 Potassium Channel
/ genetics
Long QT Syndrome
/ genetics
Male
Middle Aged
Mutation
NAV1.5 Voltage-Gated Sodium Channel
/ genetics
Pedigree
Ryanodine Receptor Calcium Release Channel
/ genetics
Young Adult
Journal
Journal of human genetics
ISSN: 1435-232X
Titre abrégé: J Hum Genet
Pays: England
ID NLM: 9808008
Informations de publication
Date de publication:
Dec 2020
Dec 2020
Historique:
received:
14
04
2020
accepted:
07
07
2020
revised:
15
06
2020
pubmed:
19
7
2020
medline:
22
6
2021
entrez:
19
7
2020
Statut:
ppublish
Résumé
Mutations in KCNQ1, KCNH2, and SCN5A are the major cause of long QT syndrome (LQTS). More than 90% of the genotyped patients have been reported to carry mutations in any of these three genes. Thanks to increasing popularity of next generation sequencer (NGS), novel CACNA1C mutations have been identified among LQTS patients without extra-cardiac phenotypes. We aimed to clarify the frequency of genotypes in LQTS patients in the era of NGS. The study comprised 160 congenital LQTS patients (71 males) registered from November 2015 to September 2018. Inclusion criteria was QTc > 460 ms and Schwartz score ≥ 3. We performed genetic analysis using target gene method by NGS and confirmed the mutations by Sanger method. The median age for genetic screening was 13 (0-68) years. Sixteen patients suffered cardiac arrest, 47 syncope, and 97 were asymptomatic. We identified genetic mutations in 111 (69.4%) patients including 6 CACNA1C (5.4% of the genotyped patients) with 4 asymptomatic patients. Five (3.1%) patients carried double mutations; three out of them with RYR2 and KCNQ1 or KCNH2. In conclusion, CACNA1C screening would be recommended even if the patient is asymptomatic to elucidate the genetic background of the LQTS patients.
Identifiants
pubmed: 32681117
doi: 10.1038/s10038-020-0805-z
pii: 10.1038/s10038-020-0805-z
doi:
Substances chimiques
CACNA1C protein, human
0
Calcium Channels, L-Type
0
ERG1 Potassium Channel
0
KCNH2 protein, human
0
KCNQ1 Potassium Channel
0
KCNQ1 protein, human
0
NAV1.5 Voltage-Gated Sodium Channel
0
RyR2 protein, human
0
Ryanodine Receptor Calcium Release Channel
0
SCN5A protein, human
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1083-1091Subventions
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 18K07875
Organisme : MEXT | Japan Society for the Promotion of Science (JSPS)
ID : 17K15999
Organisme : Ministry of Health, Labour and Welfare (Ministry of Health, Labour and Welfare, Japan)
ID : H27-032
Organisme : Ministry of Health, Labour and Welfare (Ministry of Health, Labour and Welfare, Japan)
ID : H29-055
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP17ek0109202
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP17ek0109294
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP17ek0109219
Références
Mizusawa Y, Horie M, Wilde AA. Genetic and clinical advances in congenital long QT syndrome. Circ J. 2014;78:2827–33.
doi: 10.1253/circj.CJ-14-0905
Devalla HD, Gelinas R, Aburawi EH, Beqqali A, Goyette P, Freund C, et al. TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT. EMBO Mol Med. 2016;8:1390–408.
doi: 10.15252/emmm.201505719
Reed GJ, Boczek NJ, Etheridge SP, Ackerman MJ. CALM3 mutation associated with long QT syndrome. Heart Rhythm. 2015;12:419–22.
doi: 10.1016/j.hrthm.2014.10.035
Mizusawa Y. Recent advances in genetic testing and counseling for inherited arrhythmias. J Arrhythm. 2016;32:389–97.
doi: 10.1016/j.joa.2015.12.009
Metzker ML. Sequencing technologies—the next generation. Nat Rev Genet. 2010;11:31–46.
doi: 10.1038/nrg2626
Rehm HL. Disease-targeted sequencing: a cornerstone in the clinic. Nat Rev Genet. 2013;14:295–300.
doi: 10.1038/nrg3463
Splawski I, Timothy KW, Decher N, Kumar P, Sachse FB, Beggs AH, et al. Severe arrhythmia disorder caused by cardiac L-type calcium channel mutations. Proc Natl Acad Sci USA. 2005;102:8089–96.
doi: 10.1073/pnas.0502506102
Splawski I, Timothy KW, Sharpe LM, Decher N, Kumar P, Bloise R, et al. Ca
doi: 10.1016/j.cell.2004.09.011
Boczek NJ, Best JM, Tester DJ, Giudicessi JR, Middha S, Evans JM, et al. Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ Cardiovasc Genet. 2013;6:279–89.
doi: 10.1161/CIRCGENETICS.113.000138
Fukuyama M, Wang Q, Kato K, Ohno S, Ding WG, Toyoda F, et al. Long QT syndrome type 8: novel CACNA1C mutations causing QT prolongation and variant phenotypes. Europace. 2014;16:1828–37.
doi: 10.1093/europace/euu063
Wemhoner K, Friedrich C, Stallmeyer B, Coffey AJ, Grace A, Zumhagen S, et al. Gain-of-function mutations in the calcium channel CACNA1C (Cav1.2) cause non-syndromic long-QT but not Timothy syndrome. J Mol Cell Cardiol. 2015;80:186–95.
doi: 10.1016/j.yjmcc.2015.01.002
Schwartz PJ, Crotti L, Insolia R. Long-QT syndrome: from genetics to management. Circ Arrhythm Electrophysiol. 2012;5:868–77.
doi: 10.1161/CIRCEP.111.962019
Ozawa J, Ohno S, Hisamatsu T, Itoh H, Makiyama T, Suzuki H, et al. Pediatric cohort with long QT syndrome-KCNH2 mutation carriers present late onset but severe symptoms. Circ J. 2016;80:696–702.
doi: 10.1253/circj.CJ-15-0933
Yoshinaga M, Ushinohama H, Sato S, Tauchi N, Horigome H, Takahashi H, et al. Electrocardiographic screening of 1-month-old infants for identifying prolonged QT intervals. Circ Arrhythm Electrophysiol. 2013;6:932–8.
doi: 10.1161/CIRCEP.113.000619
Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, et al. A method and server for predicting damaging missense mutations. Nat Methods. 2010;7:248–9.
doi: 10.1038/nmeth0410-248
Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res. 2003;31:3812–4.
doi: 10.1093/nar/gkg509
Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet. 2014;46:310–5.
doi: 10.1038/ng.2892
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.
doi: 10.1038/gim.2015.30
Sumitomo N. Current topics in catecholaminergic polymorphic ventricular tachycardia. J Arrhythm. 2016;32:344–51.
doi: 10.1016/j.joa.2015.09.008
Ozawa J, Ohno S, Saito H, Saitoh A, Matsuura H, Horie M. A novel CACNA1C mutation identified in a patient with Timothy syndrome without syndactyly exerts both marked loss-and-gain of function effects. HeartRhythm Case Rep. 2018;4:273–7.
doi: 10.1016/j.hrcr.2018.03.003
Schneeberger K. Using next-generation sequencing to isolate mutant genes from forward genetic screens. Nat Rev Genet. 2014;15:662–76.
doi: 10.1038/nrg3745
Cheung JW, Meli AC, Xie W, Mittal S, Reiken S, Wronska A, et al. Short-coupled polymorphic ventricular tachycardia at rest linked to a novel ryanodine receptor (RyR2) mutation: leaky RyR2 channels under non-stress conditions. Int J Cardiol. 2015;180:228–36.
doi: 10.1016/j.ijcard.2014.11.119
Fujii Y, Itoh H, Ohno S, Murayama T, Kurebayashi N, Aoki H, et al. A type 2 ryanodine receptor variant associated with reduced Ca
doi: 10.1016/j.hrthm.2016.10.015
Ozawa J, Ohno S, Fujii Y, Makiyama T, Suzuki H, Saitoh A, et al. Differential diagnosis between catecholaminergic polymorphic ventricular tachycardia and long QT syndrome type 1-modified Schwartz score. Circ J. 2018;82:2269–76.
doi: 10.1253/circj.CJ-17-1032
Saito A, Ohno S, Nuruki N, Nomura Y, Horie M, Yoshinaga M. Three cases of catecholaminergic polymorphic ventricular tachycardia with prolonged QT intervals including two cases of compound mutations. J Arrhythm. 2018;34:291–3.
doi: 10.1002/joa3.12053
Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ. Classification and reporting of potentially proarrhythmic common genetic variation in long QT syndrome genetic testing. Circulation. 2018;137:619–30.
doi: 10.1161/CIRCULATIONAHA.117.030142
Hosseini SM, Kim R, Udupa S, Costain G, Jobling R, Liston E, et al. Reappraisal of reported genes for sudden arrhythmic death. Circulation. 2018;138:1195–205.
doi: 10.1161/CIRCULATIONAHA.118.035070
Adler A, Novelli V, Amin AS, Abiusi E, Care M, Nannenberg EA, et al. An international, multicentered, evidence-based reappraisal of genes reported to cause congenital long QT syndrome. Circulation. 2020;141:418–28.
doi: 10.1161/CIRCULATIONAHA.119.043132
Takahashi K, Shimizu W, Miyake A, Nabeshima T, Nakayashiro M, Ganaha H. High prevalence of the SCN5A E1784K mutation in school children with long QT syndrome living on the Okinawa islands. Circ J. 2014;78:1974–9.
doi: 10.1253/circj.CJ-13-1516
Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M, et al. A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics. J Am Coll Cardiol. 2001;37:562–8.
doi: 10.1016/S0735-1097(00)01124-4
Harada M, Suzuki H, Ohno S, Ozawa J, Saitoh A, Horie M. Dynamic QT changes in long QT syndrome type 8. Circ J. 2018;83:1614.
doi: 10.1253/circj.CJ-18-0984
Boczek NJ, Ye D, Jin F, Tester DJ, Huseby A, Bos JM, et al. Identification and functional characterization of a novel CACNA1C-mediated cardiac disorder characterized by prolonged QT intervals with hypertrophic cardiomyopathy, congenital heart defects, and sudden cardiac death. Circ Arrhythm Electrophysiol. 2015;8:1122–32.
doi: 10.1161/CIRCEP.115.002745
Crotti L, Johnson CN, Graf E, De Ferrari GM, Cuneo BF, Ovadia M, et al. Calmodulin mutations associated with recurrent cardiac arrest in infants. Circulation. 2013;127:1009–17.
doi: 10.1161/CIRCULATIONAHA.112.001216
Makita N, Yagihara N, Crotti L, Johnson CN, Beckmann BM, Roh MS, et al. Novel calmodulin mutations associated with congenital arrhythmia susceptibility. Circ Cardiovasc Genet. 2014;7:466–74.
doi: 10.1161/CIRCGENETICS.113.000459
Napolitano C, Priori SG, Schwartz PJ, Bloise R, Ronchetti E, Nastoli J, et al. Genetic testing in the long QT syndrome: development and validation of an efficient approach to genotyping in clinical practice. JAMA. 2005;294:2975–80.
doi: 10.1001/jama.294.23.2975
Anderson CL, Delisle BP, Anson BD, Kilby JA, Will ML, Tester DJ, et al. Most LQT2 mutations reduce Kv11.1 (hERG) current by a class 2 (trafficking-deficient) mechanism. Circulation. 2006;113:365–73.
doi: 10.1161/CIRCULATIONAHA.105.570200
Furukawa T, Izumi G, Ohno S, Horie M. A Japanese family with long QT syndrome: distinct genetic and phenotypic features in children of asymptomatic parents with SCN5A and KCNQ1 mutations. Pediatr Cardiol Card Surg. 2017;33:431–7.
doi: 10.9794/jspccs.33.431
Kapa S, Tester DJ, Salisbury BA, Harris-Kerr C, Pungliya MS, Alders M, et al. Genetic testing for long-QT syndrome: distinguishing pathogenic mutations from benign variants. Circulation. 2009;120:1752–60.
doi: 10.1161/CIRCULATIONAHA.109.863076
Vyas B, Puri RD, Namboodiri N, Saxena R, Nair M, Balakrishnan P, et al. Phenotype guided characterization and molecular analysis of Indian patients with long QT syndromes. Indian Pacing Electrophysiol J. 2016;16:8–18.
doi: 10.1016/j.ipej.2016.03.003
Wollnik B, Schroeder BC, Kubisch C, Esperer HD, Wieacker P, Jentsch TJ. Pathophysiological mechanisms of dominant and recessive KVLQT1 K
doi: 10.1093/hmg/6.11.1943