Pediatric Cardiology

, Volume 40, Issue 8, pp 1679–1687 | Cite as

Reclassification of Variants of Uncertain Significance in Children with Inherited Arrhythmia Syndromes is Predicted by Clinical Factors

  • Jeffrey S. Bennett
  • Madison Bernhardt
  • Kim L. McBride
  • Shalini C. Reshmi
  • Erik Zmuda
  • Naomi J. Kertesz
  • Vidu Garg
  • Sara Fitzgerald-Butt
  • Anna N. KampEmail author
Original Article


Genetic testing is important to augment clinical diagnosis and inform management of inherited arrhythmias syndromes (IAS), but variants of uncertain significance (VUS) are common and remain a challenge in clinical practice. In 2015, American College of Medical Genetics (ACMG) published updated guidelines for interpretation of genetic results. Despite increasing understanding of human genomic variation, there are no guidelines for reinterpretation of prior genetic test results. Patients at a single tertiary children’s hospital with genetic testing for an IAS that demonstrated a VUS were re-evaluated using 2015 ACMG guidelines, clinical information, and publically available databases. Search of the electronic medical record identified 116 patients with genetic testing results available, and 24/116 (21%) harbored a VUS for an IAS. 23 unique VUS were evaluated from 12 genes. Over half of the VUS (12/23 (52%)) were reclassified using 2015 criteria, and 8 (35%) changed to pathogenic and 4 (17%) to benign. Relative risk of reclassification of VUS to a pathogenic variant in a patient with confirmed clinical diagnosis was 4.1 (95% CI 1.23–15.4). Reclassification was not associated with initial testing year. These data demonstrate 52% of VUS in children with IAS are reclassified with application of 2015 ACMG guidelines. Strength of phenotyping is associated with eventual pathogenic classification of genetic variants and periodic re-evaluation of VUS identified on genetic testing for IAS is warranted.


Genetics Arrhythmias Variants Long QT syndrome Genomics CPVT 



This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with Ethical Standards

Conflict of interest

All authors declare that they have no conflict of interest.

Informed consent

This study was a retrospective study exempt from informed consent. The study was approved by the Institutional Review Board of Nationwide Children’s Hospital, Columbus, OH.


  1. 1.
    Ackerman MJ (2015) Genetic purgatory and the cardiac channelopathies: exposing the variants of uncertain/unknown significance issue. Heart Rhythm 12(11):2325–2331. CrossRefPubMedGoogle Scholar
  2. 2.
    Bertier G, Hetu M, Joly Y (2016) Unsolved challenges of clinical whole-exome sequencing: a systematic literature review of end-users' views. BMC Med Genom 9(1):52. CrossRefGoogle Scholar
  3. 3.
    Aronson SJ, Clark EH, Varugheese M, Baxter S, Babb LJ, Rehm HL (2012) Communicating new knowledge on previously reported genetic variants. Genet Med. CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Ackerman MJ, Priori SG, Willems S, Berul C, Brugada R, Calkins H, Camm AJ, Ellinor PT, Gollob M, Hamilton R, Hershberger RE, Judge DP, Le Marec H, McKenna WJ, Schulze-Bahr E, Semsarian C, Towbin JA, Watkins H, Wilde A, Wolpert C, Zipes DP (2011) 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). Heart Rhythm 8(8):1308–1339. CrossRefPubMedGoogle Scholar
  5. 5.
    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL (2015) 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(5):405–424. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Lek M, Karczewski KJ, Minikel EV, Samocha KE, Banks E, Fennell T, O'Donnell-Luria AH, Ware JS, Hill AJ, Cummings BB, Tukiainen T, Birnbaum DP, Kosmicki JA, Duncan LE, Estrada K, Zhao F, Zou J, Pierce-Hoffman E, Berghout J, Cooper DN, Deflaux N, DePristo M, Do R, Flannick J, Fromer M, Gauthier L, Goldstein J, Gupta N, Howrigan D, Kiezun A, Kurki MI, Moonshine AL, Natarajan P, Orozco L, Peloso GM, Poplin R, Rivas MA, Ruano-Rubio V, Rose SA, Ruderfer DM, Shakir K, Stenson PD, Stevens C, Thomas BP, Tiao G, Tusie-Luna MT, Weisburd B, Won HH, Yu D, Altshuler DM, Ardissino D, Boehnke M, Danesh J, Donnelly S, Elosua R, Florez JC, Gabriel SB, Getz G, Glatt SJ, Hultman CM, Kathiresan S, Laakso M, McCarroll S, McCarthy MI, McGovern D, McPherson R, Neale BM, Palotie A, Purcell SM, Saleheen D, Scharf JM, Sklar P, Sullivan PF, Tuomilehto J, Tsuang MT, Watkins HC, Wilson JG, Daly MJ, MacArthur DG (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291. CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Clemens DJ, Lentino AR, Kapplinger JD, Ye D, Zhou W, Tester DJ, Ackerman MJ (2017) Using the genome aggregation database, computational pathogenicity prediction tools, and patch clamp heterologous expression studies to demote previously published long QT syndrome type 1 mutations from pathogenic to benign. Heart Rhythm. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Refsgaard L, Holst AG, Sadjadieh G, Haunso S, Nielsen JB, Olesen MS (2012) High prevalence of genetic variants previously associated with LQT syndrome in new exome data. Eur J Hum Genet 20(8):905–908. CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Lahrouchi N, Raju H, Lodder EM, Papatheodorou E, Ware JS, Papadakis M, Tadros R, Cole D, Skinner JR, Crawford J, Love DR, Pua CJ, Soh BY, Bhalshankar JD, Govind R, Tfelt-Hansen J, Winkel BG, van der Werf C, Wijeyeratne YD, Mellor G, Till J, Cohen MC, Tome-Esteban M, Sharma S, Wilde AAM, Cook SA, Bezzina CR, Sheppard MN, Behr ER (2017) Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome. J Am Coll Cardiol 69(17):2134–2145. CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Ackerman JP, Bartos DC, Kapplinger JD, Tester DJ, Delisle BP, Ackerman MJ (2016) The promise and peril of precision medicine: phenotyping still matters most. Mayo Clin Proc. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C (2013) Executive summary: HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes. Heart Rhythm 10(12):e85–e108. CrossRefPubMedGoogle Scholar
  12. 12.
    Schwartz PJ, Crotti L (2011) QTc behavior during exercise and genetic testing for the long-QT syndrome. Circulation 124(20):2181–2184. CrossRefPubMedGoogle Scholar
  13. 13.
    Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C (2013) HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 10(12):1932–1963. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Antzelevitch C, Brugada P, Borggrefe M, Brugada J, Brugada R, Corrado D, Gussak I, LeMarec H, Nademanee K, Perez Riera AR, Shimizu W, Schulze-Bahr E, Tan H, Wilde A (2005) Brugada syndrome: report of the second consensus conference. Heart Rhythm 2(4):429–440CrossRefGoogle Scholar
  15. 15.
    Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN (2017) The human gene mutation database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet 136(6):665–677. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Tester DJ, Ackerman MJ (2012) The molecular autopsy: should the evaluation continue after the funeral? Pediatr Cardiol 33(3):461–470. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Schwartz PJ, Stramba-Badiale M, Crotti L, Pedrazzini M, Besana A, Bosi G, Gabbarini F, Goulene K, Insolia R, Mannarino S, Mosca F, Nespoli L, Rimini A, Rosati E, Salice P, Spazzolini C (2009) Prevalence of the congenital long-QT syndrome. Circulation 120(18):1761–1767. CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Watanabe H, Minamino T (2016) Genetics of brugada syndrome. J Hum Genet 61(1):57–60. CrossRefPubMedGoogle Scholar
  19. 19.
    Cerrone M, Napolitano C, Priori SG (2009) Catecholaminergic polymorphic ventricular tachycardia: A paradigm to understand mechanisms of arrhythmias associated to impaired Ca(2+) regulation. Heart Rhythm 6(11):1652–1659. CrossRefPubMedGoogle Scholar
  20. 20.
    Whiffin N, Minikel E, Walsh R, O'Donnell-Luria AH, Karczewski K, Ing AY, Barton PJR, Funke B, Cook SA, MacArthur D, Ware JS (2017) Using high-resolution variant frequencies to empower clinical genome interpretation. Genet Med 19(10):1151–1158. CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Tobelaim WS, Dvir M, Lebel G, Cui M, Buki T, Peretz A, Marom M, Haitin Y, Logothetis DE, Hirsch JA, Attali B (2017) Competition of calcified calmodulin N lobe and PIP2 to an LQT mutation site in Kv7.1 channel. Proc Natl Acad Sci USA 114(5):E869–E878. CrossRefGoogle Scholar
  22. 22.
    Ohno S, Zankov DP, Yoshida H, Tsuji K, Makiyama T, Itoh H, Akao M, Hancox JC, Kita T, Horie M (2007) N- and C-terminal KCNE1 mutations cause distinct phenotypes of long QT syndrome. Heart Rhythm 4(3):332–340. CrossRefPubMedGoogle Scholar
  23. 23.
    Du C, El Harchi A, Zhang H, Hancox JC (2013) Modification by KCNE1 variants of the hERG potassium channel response to premature stimulation and to pharmacological inhibition. Physiol Rep 1(6):e00175. CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chevalier P, Bellocq C, Millat G, Piqueras E, Potet F, Schott JJ, Baro I, Lemarec H, Barhanin J, Rousson R, Rodriguez-Lafrasse C (2007) Torsades de pointes complicating atrioventricular block: evidence for a genetic predisposition. Heart Rhythm 4(2):170–174. CrossRefPubMedGoogle Scholar
  25. 25.
    Novak A, Barad L, Lorber A, Gherghiceanu M, Reiter I, Eisen B, Eldor L, Itskovitz-Eldor J, Eldar M, Arad M, Binah O (2015) Functional abnormalities in iPSC-derived cardiomyocytes generated from CPVT1 and CPVT2 patients carrying ryanodine or calsequestrin mutations. J Cell Mol Med 19(8):2006–2018. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Kimlicka L, Tung CC, Carlsson AC, Lobo PA, Yuchi Z, Van Petegem F (2013) The cardiac ryanodine receptor N-terminal region contains an anion binding site that is targeted by disease mutations. Structure 21(8):1440–1449. CrossRefPubMedGoogle Scholar
  27. 27.
    Domingo D, Neco P, Fernandez-Pons E, Zissimopoulos S, Molina P, Olague J, Suarez-Mier MP, Lai FA, Gomez AM, Zorio E (2015) Non-ventricular, clinical, and functional features of the RyR2(R420Q) mutation causing catecholaminergic polymorphic ventricular tachycardia. Revista espanola de cardiologia (English ed) 68(5):398–407. CrossRefGoogle Scholar
  28. 28.
    Giudicessi JR, Wilde AAM, Ackerman MJ (2018) The genetic architecture of long QT syndrome: a critical reappraisal. Trends Cardiovasc Med. CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Shanks GW, Tester DJ, Nishtala S, Evans JM, Ackerman MJ (2017) Genomic triangulation and coverage analysis in whole-exome sequencing-based molecular autopsies. Circulation Cardiovasc Genet. CrossRefGoogle Scholar
  30. 30.
    Bartels ED, Tfelt-Hansen J, Winkel BG (2017) Genomic triangulation in sudden unexplained death in the young: The way to go? Circulation Cardiovasc Genet. CrossRefGoogle Scholar
  31. 31.
    Giudicessi JR, Roden DM, Wilde AAM, Ackerman MJ (2018) Classification and reporting of potentially proarrhythmic common genetic variation in long QT syndrome genetic testing. Circulation 137(6):619–630. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Lieve KV, Williams L, Daly A, Richard G, Bale S, Macaya D, Chung WK (2013) Results of genetic testing in 855 consecutive unrelated patients referred for long QT syndrome in a clinical laboratory. Genet Test Mol Biomark 17(7):553–561. CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Jeffrey S. Bennett
    • 1
    • 2
  • Madison Bernhardt
    • 3
  • Kim L. McBride
    • 1
    • 4
    • 5
  • Shalini C. Reshmi
    • 1
    • 6
  • Erik Zmuda
    • 1
    • 6
  • Naomi J. Kertesz
    • 1
    • 2
  • Vidu Garg
    • 1
    • 2
    • 5
  • Sara Fitzgerald-Butt
    • 7
  • Anna N. Kamp
    • 1
    • 2
    Email author
  1. 1.Department of PediatricsThe Ohio State University College of MedicineColumbusUSA
  2. 2.The Heart CenterNationwide Children’s HospitalColumbusUSA
  3. 3.Department of Medical GeneticsSt. Luke’s Mountain States Tumor InstituteBoiseUSA
  4. 4.Division of Genetic and Genomic MedicineNationwide Children’s HospitalColumbusUSA
  5. 5.The Center for Cardiovascular ResearchNationwide Children’s HospitalColumbusUSA
  6. 6.Department of Pathology and Laboratory MedicineNationwide Children’s HospitalColumbusUSA
  7. 7.Department of Medical and Molecular GeneticsIndiana University School of MedicineIndianapolisUSA

Personalised recommendations