Ann Lab Med.  2018 Jan;38(1):54-58. 10.3343/alm.2018.38.1.54.

Application of Multigene Panel Sequencing in Patients with Prolonged Rate-corrected QT Interval and No Pathogenic Variants Detected in KCNQ1, KCNH2, and SCN5A

• Seo SH
• Kim SY
• Cho SI
• Park H
• Lee S
• Choi JM
• Kim MJ
• Lee JS
• Ahn KJ
• Song MK
• Bae EJ
• Park SS
• Seong MW

• KMID: 2397603
• DOI: http://doi.org/10.3343/alm.2018.38.1.54

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.

Keyword

Multigene panel sequencing; Prolonged heart rate-corrected QT interval; Long QT syndrome

MeSH Terms

Cardiomyopathy, Dilated
Heart
Heart Diseases
Humans
Long QT Syndrome
Mass Screening
Molecular Biology
Ryanodine Receptor Calcium Release Channel
Tachycardia, Ventricular
Ryanodine Receptor Calcium Release Channel

Reference

1. Alders M, Christiaans I. Long QT Syndrome. In : Pagon RA, Adam MP, editors. GeneReviews(R). Seattle (WA): niversity of Washington;1993. p. 1993–2017.

2. Giudicessi JR, Ackerman MJ. Genotype- and phenotype-guided management of congenital long QT syndrome. Curr Probl Cardiol. 2013; 38:417–455. PMID: 24093767.

3. Itoh H, Crotti L, Aiba T, Spazzolini C, Denjoy I, Fressart V, et al. The genetics underlying acquired long QT syndrome: impact for genetic screening. Eur Heart J. 2016; 37:1456–1464. PMID: 26715165.

4. 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; 17:405–424. PMID: 25741868.

5. 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; 8:1122–1132. PMID: 26253506.

6. D'Adamo P, Fassone L, Gedeon A, Janssen EA, Bione S, Bolhuis PA, et al. The X-linked gene G4.5 is responsible for different infantile dilated cardiomyopathies. Am J Hum Genet. 1997; 61:862–867. PMID: 9382096.

7. Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, et al. 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). Europace. 2011; 13:1077–1109. PMID: 21810866.

8. Lieve KV, Williams L, Daly A, Richard G, Bale S, Macaya D, et al. Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomarkers. 2013; 17:553–561. PMID: 23631430.

9. Stattin EL, Bostrom IM, Winbo A, Cederquist K, Jonasson J, Jonsson BA, et al. Founder mutations characterise the mutation panorama in 200 Swedish index cases referred for Long QT syndrome genetic testing. BMC Cardiovasc Disord. 2012; 12:95. PMID: 23098067.

10. Kauferstein S, Kiehne N, Erkapic D, Schmidt J, Hamm CW, Bratzke H, et al. A novel mutation in the cardiac ryanodine receptor gene (RyR2) in a patient with an unequivocal LQTS. Int J Cardiol. 2011; 146:249–250. PMID: 21126784.

11. Shigemizu D, Aiba T, Nakagawa H, Ozaki K, Miya F, Satake W, et al. Exome Analyses of Long QT Syndrome Reveal Candidate Pathogenic Mutations in Calmodulin-Interacting Genes. PLoS One. 2015; 10:e0130329. PMID: 26132555.

12. Ishikawa T, Sato A, Marcou CA, Tester DJ, Ackerman MJ, Crotti L, et al. A novel disease gene for Brugada syndrome: sarcolemmal membrane-associated protein gene mutations impair intracellular trafficking of hNav1.5. Circ Arrhythm Electrophysiol. 2012; 5:1098–1107. PMID: 23064965.

13. Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, et al. 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. 2017; 19:249–255. PMID: 27854360.

14. Nakano Y, Shimizu W. Genetics of long-QT syndrome. J Hum Genet. 2016; 61:51–55. PMID: 26108145.