Unexplained cardiac arrest: a tale of conflicting interpretations of KCNQ1 genetic test results
Unexplained cardiac arrest (UCA) is often the first manifestation of an inherited arrhythmogenic disease. Genetic testing in UCA is challenging due to the complexities of variant interpretation in the absence of supporting cardiac phenotype. We aimed to investigate if a KCNQ1 variant [p.(Pro64_Pro70del)], previously reported as pathogenic, contributes to the long-QT syndrome phenotype, co-segregates with disease or affects KCNQ1 function in vitro.
DNA was extracted from peripheral blood of a 22-year-old male after resuscitation from UCA. Targeted exome sequencing was performed using the TruSight-One Sequencing Panel (Illumina). Variants in 190 clinically relevant cardiac genes with minor allele frequency < 1% were analyzed according to the guidelines of the American College of Medical Genetics. Functional characterization was performed using site-directed mutagenesis, expression in Xenopus laevis oocytes using the two-electrode voltage-clamp technique.
The 12-lead ECG, transthoracic echocardiography and coronary angiography after resuscitation showed no specific abnormalities. Two variants were identified: c.190_210del in-frame deletion in KCNQ1 (p.Pro64_Pro70del), reported previously as pathogenic and c.2431C > A in PKP2 (p.Arg811Ser), classified as likely benign. Two asymptomatic family members with no evident phenotype hosted the KCNQ1 variant. Functional studies showed that the wild-type and mutant channels have no significant differences in current levels, conductance-voltage relationships, as well as activation and deactivation kinetics, in the absence and presence of the auxiliary subunit KCNE1.
Based on our data and previous reports, available evidence is insufficient to consider the variant KCNQ1:c.190_210del as pathogenic. Our findings call for cautious interpretation of genetic tests in UCA in the absence of a clinical phenotype.
KeywordsVentricular fibrillation Ion channel Genetics Arrhythmia Sudden cardiac death
This work was supported by the Swiss Heart Foundation (AMD). SAP was supported by a Lundbeck Foundation Fellowship (R139-2012-12390) and a Carlsberg Foundation Distinguished Associate Professor Fellowship (CF16-0504). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors declare that they have no conflict of interest.
- 1.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. https://doi.org/10.1016/j.hrthm.2011.05.020 CrossRefPubMedGoogle Scholar
- 2.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, Committee ALQA. (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. https://doi.org/10.1038/gim.2015.30 CrossRefPubMedPubMedCentralGoogle Scholar
- 7.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, Exome Aggregation C (2016) Analysis of protein-coding genetic variation in 60,706 humans. Nature 536(7616):285–291. https://doi.org/10.1038/nature19057 CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Kapplinger JD, Tester DJ, Salisbury BA, Carr JL, Harris-Kerr C, Pollevick GD, Wilde AA, Ackerman MJ (2009) Spectrum and prevalence of mutations from the first 2,500 consecutive unrelated patients referred for the FAMILION long QT syndrome genetic test. Heart Rhythm 6(9):1297–1303. https://doi.org/10.1016/j.hrthm.2009.05.021 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Fressart V, Duthoit G, Donal E, Probst V, Deharo JC, Chevalier P, Klug D, Dubourg O, Delacretaz E, Cosnay P, Scanu P, Extramiana F, Keller D, Hidden-Lucet F, Simon F, Bessirard V, Roux-Buisson N, Hebert JL, Azarine A, Casset-Senon D, Rouzet F, Lecarpentier Y, Fontaine G, Coirault C, Frank R, Hainque B, Charron P (2010) Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia/cardiomyopathy: spectrum of mutations and clinical impact in practice. Europace. 12 (6):861–868. https://doi.org/10.1093/europace/euq104 CrossRefPubMedGoogle Scholar
- 10.Klauke B, Kossmann S, Gaertner A, Brand K, Stork I, Brodehl A, Dieding M, Walhorn V, Anselmetti D, Gerdes D, Bohms B, Schulz U, Zu Knyphausen E, Vorgerd M, Gummert J, Milting H (2010) De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy. Human Mol Genet 19(23):4595–4607. https://doi.org/10.1093/hmg/ddq387 CrossRefGoogle Scholar
- 11.Tan BY, Jain R, den Haan AD, Chen Y, Dalal D, Tandri H, Amat-Alarcon N, Daly A, Tichnell C, James C, Calkins H, Judge DP (2010) Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Cardiovasc Translational Res 3(6):663–673. https://doi.org/10.1007/s12265-010-9224-4 CrossRefGoogle Scholar
- 12.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. https://doi.org/10.1016/j.hrthm.2013.05.014 CrossRefPubMedGoogle Scholar
- 13.Mellor G, Laksman ZWM, Tadros R, Roberts JD, Gerull B, Simpson CS, Klein GJ, Champagne J, Talajic M, Gardner M, Steinberg C, Arbour L, Birnie DH, Angaran P, Leather R, Sanatani S, Chauhan VS, Seifer C, Healey JS, Krahn AD (2017) Genetic Testing in the Evaluation of Unexplained Cardiac Arrest: From the CASPER (Cardiac Arrest Survivors With Preserved Ejection Fraction Registry). Circul Cardiovasc Genet 10 (3). https://doi.org/10.1161/CIRCGENETICS.116.001686
- 14.Jimenez-Jaimez J, Peinado R, Grima EZ, Segura F, Morina P, Sanchez Munoz JJ, Mazuelos F, Cozar R, Gimeno JR, Heras RP, Monserrat L, Domingo D, Ortiz-Genga M, Fernandez Pastor J, Alvarez M, Tercedor L (2015) Diagnostic approach to unexplained cardiac arrest (from the FIVI-Gen study). Am J Cardiol 116(6):894–899. https://doi.org/10.1016/j.amjcard.2015.06.030 CrossRefPubMedGoogle Scholar
- 15.Song JS, Kang JS, Kim YE, Park SJ, Park KM, Huh J, Kim JS, Cho H, Ki CS, On YK (2017) Identification of pathogenic variants in genes related to channelopathy and cardiomyopathy in Korean sudden cardiac arrest survivors. J Hum Genet 62(6):615–620. https://doi.org/10.1038/jhg.2017.8 CrossRefPubMedGoogle Scholar
- 16.Bagnall RD, Weintraub RG, Ingles J, Duflou J, Yeates L, Lam L, Davis AM, Thompson T, Connell V, Wallace J, Naylor C, Crawford J, Love DR, Hallam L, White J, Lawrence C, Lynch M, Morgan N, James P, du Sart D, Puranik R, Langlois N, Vohra J, Winship I, Atherton J, McGaughran J, Skinner JR, Semsarian C (2016) A prospective study of sudden cardiac death among children and young adults. N Engl J Med 374(25):2441–2452. https://doi.org/10.1056/NEJMoa1510687 CrossRefPubMedGoogle Scholar
- 20.Gerull B, Heuser A, Wichter T, Paul M, Basson CT, McDermott DA, Lerman BB, Markowitz SM, Ellinor PT, MacRae CA, Peters S, Grossmann KS, Drenckhahn J, Michely B, Sasse-Klaassen S, Birchmeier W, Dietz R, Breithardt G, Schulze-Bahr E, Thierfelder L (2004) Mutations in the desmosomal protein plakophilin-2 are common in arrhythmogenic right ventricular cardiomyopathy. Nat Genet 36(11):1162–1164. https://doi.org/10.1038/ng1461 CrossRefPubMedGoogle Scholar
- 21.Leinonen JT, Crotti L, Djupsjobacka A, Castelletti S, Junna N, Ghidoni A, Tuiskula AM, Spazzolini C, Dagradi F, Viitasalo M, Kontula K, Kotta MC, Widen E, Swan H, Schwartz PJ (2018) The genetics underlying idiopathic ventricular fibrillation: a special role for catecholaminergic polymorphic ventricular tachycardia? Int J Cardiol 250:139–145. https://doi.org/10.1016/j.ijcard.2017.10.016 CrossRefPubMedGoogle Scholar