Application of Multigene Panel Sequencing in Patients with Prolonged Rate-corrected QT Interval and No Pathogenic Variants Detected in KCNQ1, KCNH2, and SCN5A
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Long QT syndrome (LQTS) is an inherited cardiac disease characterized by a prolonged heart rate-corrected QT (QTc) interval. We investigated the genetic causes in patients with prolonged QTc intervals who were negative for pathogenic variants in three major LQTS-related genes (KCNQ1, KCNH2, and SCN5A). Molecular genetic testing was performed using a panel including 13 LQTS-related genes and 67 additional genes implicated in other cardiac diseases. Overall, putative genetic causes of prolonged QTc interval were identified in three of the 30 patients (10%). Among the LQTS-related genes, we detected a previously reported pathogenic variant, CACNA1C c.1552C>T, responsible for cardiac-only Timothy syndrome. Among the genes related to other cardiac diseases, a likely pathogenic variant, RYR2 c.11995A>G, was identified in a patient with catecholaminergic polymorphic ventricular tachycardia. Another patient who developed dilated cardiomyopathy with prolonged QTc interval was found to carry a likely pathogenic variant, TAZ c.718G>A, associated with infantile dilated cardiomyopathy. Comprehensive screening of genetic variants using multigene panel sequencing enables detection of genetic variants with a possible involvement in QTc interval prolongation, thus uncovering unknown molecular mechanisms underlying LQTS
Abstract
Long QT syndrome (LQTS) is an inherited cardiac disease characterized by a prolonged heart rate-corrected QT (QTc) interval. We investigated the genetic causes in patients with prolonged QTc intervals who were negative for pathogenic variants in three major LQTS-related genes (KCNQ1, KCNH2, and SCN5A). Molecular genetic testing was performed using a panel including 13 LQTS-related genes and 67 additional genes implicated in other cardiac diseases. Overall, putative genetic causes of prolonged QTc interval were identified in three of the 30 patients (10%). Among the LQTS-related genes, we detected a previously reported pathogenic variant, CACNA1C c.1552C>T, responsible for cardiac-only Timothy syndrome. Among the genes related to other cardiac diseases, a likely pathogenic variant, RYR2 c.11995A>G, was identified in a patient with catecholaminergic polymorphic ventricular tachycardia. Another patient who developed dilated cardiomyopathy with prolonged QTc interval was found to carry a likely pathogenic variant, TAZ c.718G>A, associated with infantile dilated cardiomyopathy. Comprehensive screening of genetic variants using multigene panel sequencing enables detection of genetic variants with a possible involvement in QTc interval prolongation, thus uncovering unknown molecular mechanisms underlying LQTS
참고문헌 (14)
- Alders M, "GeneReviews(R)", pp.1993~2017 (1993), University of Washington
- Giudicessi JR, "Genotype- and phenotype-guided management of congenital long QT syndrome", Curr Probl Cardiol, 38, pp.417~455 (2013)[DOI]
- Itoh H, "The genetics underlying acquired long QT syndrome: impact for genetic screening", Eur Heart J, 37, pp.1456~1464 (2016)[DOI]
- Richards S, "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, 17, pp.405~424 (2015)[DOI]
- Boczek NJ, "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, 8, pp.1122~1132 (2015)[DOI]
- D'Adamo P, "The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies", Am J Hum Genet, 61, pp.862~867 (1997)[DOI]
- Ackerman MJ, "HRS", EHRA expert consensus statement on the state of genetic testing for the channelopathies and cardiomyopathies: this document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA), 2011, pp.13, 1077~1109
- Lieve KV, "Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory", Genet Test Mol Biomarkers, 17, pp.553~561 (2013)[DOI]
- Stattin EL, "Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing", BMC Cardiovasc Disord, 12, pp.95~ (2012)[DOI]
- Kauferstein S, "A novel mutation in the cardiac ryanodine receptor gene (RyR2) in a patient with an unequivocal LQTS", Int J Cardiol, 146, pp.249~250 (2011)[DOI]
- Shigemizu D, "Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes", PLoS One, 10, pp.e0130329~ (2015)[DOI]
- Ishikawa T, "A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5", Circ Arrhythm Electrophysiol, 5, pp.1098~1107 (2012)[DOI]
- Kalia SS, "Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics", Genet Med, 19, pp.249~255 (2017)[DOI]
- Nakano Y, "Genetics of long-QT syndrome", J Hum Genet, 61, pp.51~55 (2016)[DOI]