A novel variant in KCNQ1 associated with short QT syndrome

Abstract

Short QT syndrome (SQTS) is a rare and relatively recently discovered cardiac channelopathy associated with atrial and ventricular fibrillation and sudden cardiac death. A short QT interval on electrocardiogram (ECG) is particularly rare in the pediatric population, with a reported incidence of 0.05%.1Bjerregaard P. Diagnosis and management of short QT syndrome.Heart Rhythm. 2018; 15: 1261-1267Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar This autosomal dominant condition has been associated with 20 different variants in 9 different genes.1Bjerregaard P. Diagnosis and management of short QT syndrome.Heart Rhythm. 2018; 15: 1261-1267Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Associated genes include those encoding potassium channels (KCNH2, KCNQ1, KCNJ2) and cation channels (SCN5A), genes encoding L-type calcium channel subunits (CACNA1C, CACNB2b, CACNA2D1), and, less commonly, anion exchanger mutations such as SLC4A3.1Bjerregaard P. Diagnosis and management of short QT syndrome.Heart Rhythm. 2018; 15: 1261-1267Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar There are, however, a substantial number of patients clinically diagnosed with SQTS for whom no causative genetic mutation is identified. We present a case of ventricular fibrillation cardiac arrest with a suspiciously short but initially nondiagnostic QTc (383 ms). Clinical genetic testing revealed a novel variant in the KCNQ1 gene, which we believe likely represents a novel variant associated with SQTS. A previously healthy 10-year-old girl was vacationing with her family on the beach when she experienced a ventricular fibrillation sudden cardiac arrest. She told her father she felt nauseous and then collapsed and became unconscious. She received bystander cardiopulmonary resuscitation and had an automated external defibrillator placed, which recorded ventricular fibrillation. She converted to pulseless electrical activity after a 120 joule shock, and subsequently to an organized rhythm (Figure 1). She had return of spontaneous circulation after 10 minutes and was transferred to a local hospital. She had no history of syncope or palpitations. She was active in sports and able to keep up with other children her age without difficulty. The patient’s mother, maternal grandmother, and maternal great-grandmother all had a history of atrial fibrillation. Her mother ultimately underwent ablation for her atrial fibrillation as a teenager, but had not followed up with a cardiologist in a number of years. A paternal first cousin died suddenly at 4 months of age of an unknown etiology that was ultimately attributed to sudden infant death syndrome. Her initial physical examination was unremarkable and remained so throughout her hospitalization. An initial transthoracic echocardiogram performed the day of her arrest was notable for an ejection fraction of 35% with a structurally normal heart. Her initial ECG showed normal sinus rhythm at 103 beats/min with a QT of 292 ms and a QTc of 383 ms calculated using Bazett’s formula (Figure 2). There were no electrolyte abnormalities and a repeat echocardiogram the following day demonstrated normal function with an ejection fraction of 55%. Cardiac magnetic resonance imaging showed no evidence of myocarditis or cardiomyopathy. Telemetry monitoring and serial ECGs were significant for a short QT interval with a minimal QTc of 344 ms (Figure 2). Our patient’s minimal QT interval was 82% of her predicted QT interval of 369 ms (calculated as proposed by Rautaharju)2Gollob M.H. Redpath C.J. Roberts J.D. The short QT syndrome: proposed diagnostic criteria.J Am Coll Cardiol. 2011; 57: 802-812Crossref PubMed Scopus (196) Google Scholar and while her Tpeak-Tend was within the normal range at 72 ms, her Tp-e/QT ratio was slightly elevated at 0.26. Graded exercise testing demonstrated a lack of adaptation of the QT interval to exercise and increasing heart rates, with a baseline QTc of 361 ms and a shortest QTc of 353 ms seen at peak exercise. There was also a blunted adaptation of the QT interval in recovery and decreasing heart rates, with a QTc of 321 ms at 1 minute into recovery and a QTc of 372 ms at 7 minutes into recovery. A subcutaneous implantable cardioverter-defibrillator (ICD) was placed for secondary prevention. During the procedure defibrillation threshold testing was performed, ventricular fibrillation was induced, and the ICD delivered a successful shock with return to sinus rhythm. She has been doing well since discharge, with complete cardiovascular and neurologic recovery at 6 month follow-up, no symptoms, and no ICD therapies. During her admission a 114-gene arrhythmia and cardiomyopathy gene panel (Invitae, San Francisco, CA) was ordered and revealed 3 variants of unknown significance in KCNQ1 (NM_000218.2: c.836T>G, p.Phe279Cys), RYR2 (NM_001035.2: c.13291G>A, p.Glu4431Lys), and TTN (NM_001267550.2: c.101117T>C, p.Val33706Ala). The performing laboratory noted the variant in RYR2 was predicted to be tolerated by in silico prediction tools. It was noted that the variant had been reported in 1 individual with long QT syndrome3Berge K.E. Haugaa K.H. Fruh A. et al.Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers.Scand J Clin Lab Invest. 2008; 68: 362-368Crossref PubMed Scopus (46) Google Scholar and in 1 individual with sudden cardiac death.4Wang D. Shah K.R. Um S.Y. et al.Cardiac channelopathy testing in 274 ethnically diverse sudden unexplained deaths.Forensic Sci Int. 2014; 237: 90-99Crossref PubMed Google Scholar However, this variant is also present in population databases, including in a European non-Finnish population with an allele frequency of 0.05% (51/106,610 alleles) in gnomAD (Table 1).5Lek M. Karczewski K.J. Minikel E.V. et al.Analysis of protein-coding genetic variation in 60,706 humans.Nature. 2016; 536: 285-291Crossref PubMed Google Scholar The TTN p.Val33706Ala missense variant occurs in the M band region of the gene and was identified once in gnomAD (allele frequency of 0.0009% in European non-Finnish population); it has not been published in association with disease.Table 1Genetic variant dataKCNQ1c.836T>Gp.Phe279CysRYR2 c.13291G>Ap.Glu4431LysTTN c.101117T>Cp.Val33706AlagnomAD frequency Total allelesAbsent54:242,8621:248,758 European non-Finnish allelesAbsent51:106,6101:112,628In silico tools†As assessed through UCSC genome browser (https://genome.ucsc.edu/index.html).15 SIFTDamagingToleratedN/A PolyPhen-2Possibly damagingBenignN/A MutationTasterDisease-causingDisease-causingN/ASpecies conservation†As assessed through UCSC genome browser (https://genome.ucsc.edu/index.html).15,‡Species conservation data provided for the wild-type amino acid corresponding to nucleotide position. HumanPheGluVal RhesusPheGluVal MousePheGluVal DogPheGluVal ElephantPheGluVal ChickenPhe=Val Xenopus tropicalisPhe=Val ZebrafishPheSerVal LampreyPhe=ValN/A = not available.Double line (=) indicates unalignable bases in the region.† As assessed through UCSC genome browser (https://genome.ucsc.edu/index.html).15Haeussler M. Zweig A.S. Tyner C. et al.The UCSC Genome Browser database: 2019 update.Nucleic Acids Res. 2019; 47: D853-D858Crossref PubMed Scopus (273) Google Scholar‡ Species conservation data provided for the wild-type amino acid corresponding to nucleotide position. Open table in a new tab N/A = not available. Double line (=) indicates unalignable bases in the region. The novel KCNQ1 p.Phe279Cys variant has not been reported in population databases, and has not been previously published in association with disease. The variant has been shown to impact KCNQ1 functionality by shifting the voltage dependence of activation in the hyperpolarizing direction.6Nakajo K. Kubo Y. Steric hindrance between S4 and S5 of the KCNQ1/KCNE1 channel hampers pore opening.Nat Commun. 2014; 5: 4100Crossref PubMed Scopus (22) Google Scholar This results in a gain-of-function effect, with a greater fraction of the channels open at a given voltage compared to the wild-type channel. As has been shown in other KCNQ1 variants associated with gain-of-function mutations, augmentation of these outward repolarizing currents has been shown to decrease the action potential duration and lead to a shorter QT interval. The phenylalanine residue at this position is highly conserved, and in silico prediction tools predict that the variant is likely to be disruptive. Another variant at this position, p.Phe279Ile, has previously been published in association with SQTS in another individual, with functional data demonstrating a gain-of-function effect.7Moreno C. Oliveras A. de la Cruz A. et al.A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome.Cardiovasc Res. 2015; 107: 613-623Crossref PubMed Google Scholar Our patient’s father had a normal QT and QTc on his ECG and his genetic testing was negative for our patient’s known KCNQ1 variant. Her mother had a short QT interval on her ECG of 322 ms and a QTc of 327 ms (Figure 2C) at 62 beats/min, and her genetic testing was positive for the same KCNQ1 variant seen in our patient. Our patient presented with a ventricular fibrillation arrest with a structurally normal heart and initial testing that did not identify an obvious diagnosis. As her workup progressed, serial ECGs were obtained and revealed several ECGs with short corrected QT intervals ranging from 344 ms to 383 ms. Although her initial QT interval was in the normal range, subsequent QTc intervals have consistently been less than 360 ms. Her telemetry during her hospitalization was reviewed as part of her investigation and showed a short QT interval at a wide range of heart rates. Her exercise testing also showed abnormal adaptation of the QT interval to exercise, which has been seen in SQTS and may be secondary to enhanced repolarization and limited repolarization reserve.1Bjerregaard P. Diagnosis and management of short QT syndrome.Heart Rhythm. 2018; 15: 1261-1267Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Additionally, her QT interval was less than 88% (2 standard deviations below the predicted value) of her QTp2 and her Tp-e/QT ratio was elevated compared to controls, with a Tpeak-Tend within the normal range8Gupta P. Patel C. Patel H. et al.T(p-e)/QT ratio as an index of arrhythmogenesis.J Electrocardiol. 2008; 41: 567-574Crossref PubMed Scopus (348) Google Scholar; all of these findings have been seen in SQTS. Owing to the relatively small number of patients with SQTS, there continues to be some debate surrounding the diagnostic criteria. Her testing is consistent with SQTS based on the 2013 HRS/EHRA/APHRS expert consensus statement9Priori S.G. Wilde A.A. Horie M. et al.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. 2013; 10: 1932-1963Abstract Full Text Full Text PDF PubMed Scopus (1039) Google Scholar (QTc less than 360 ms and survival of a ventricular fibrillation episode in the absence of heart disease) and the proposed diagnostic scoring system put forward by Gollob and colleagues2Gollob M.H. Redpath C.J. Roberts J.D. The short QT syndrome: proposed diagnostic criteria.J Am Coll Cardiol. 2011; 57: 802-812Crossref PubMed Scopus (196) Google Scholar (high probability of SQTS with a score of 4: 1 point for QTc less than 370, 2 points for history of sudden cardiac arrest or documented ventricular fibrillation, and 1 point for mutation of undetermined significance in a culprit gene). Genetic testing was performed in accordance with the 2011 HRS/EHRA expert consensus statement10Ackerman M.J. Priori S.G. Willems S. 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).Heart Rhythm. 2011; 8: 1308-1339Abstract Full Text Full Text PDF PubMed Scopus (679) Google Scholar based on the patient’s clinical history and electrocardiographic phenotype. To date, a causative variant has been found in less than 20% of patients who have undergone genetic testing for SQTS evaluation,1Bjerregaard P. Diagnosis and management of short QT syndrome.Heart Rhythm. 2018; 15: 1261-1267Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar highlighting the importance of continued investigation. The majority of variants described to date are gain-of-function variants in the rapid, inward, and slow delayed rectifier potassium currents, resulting in increased potassium efflux during the plateau phase. This leads to accelerated repolarization and shortened atrial and ventricular action potential duration, increasing arrhythmia susceptibility and sudden death.11Tse G. Chan Y.W. Keung W. Yan B.P. Electrophysiological mechanisms of long and short QT syndromes.Int J Cardiol Heart Vasc. 2017; 14: 8-13PubMed Google Scholar There have been several variants in patients with SQTS identified in the KCNQ1 gene, resulting in amino acid changes at 6 different codons. Our patient had 3 variants classified by the performing laboratory as having uncertain significance. Pathogenic variants in RYR2 are typically associated with risk for catecholaminergic polymorphic ventricular tachycardia; the RYR2 variant identified in our patient is present in population databases at an allele frequency far exceeding estimated disease prevalence.12Paludan-Muller C. Ahlberg G. Ghouse J. et al.Integration of 60,000 exomes and ACMG guidelines question the role of catecholaminergic polymorphic ventricular tachycardia-associated variants.Clin Genet. 2017; 91: 63-72Crossref PubMed Scopus (0) Google Scholar Furthermore, our patient had no evidence of catecholaminergic polymorphic ventricular tachycardia on clinical evaluation. Although specific variants in TTN, mainly truncating variants in the A band region,13Herman D.S. Lam L. Taylor M.R. et al.Truncations of titin causing dilated cardiomyopathy.N Engl J Med. 2012; 366: 619-628Crossref PubMed Scopus (733) Google Scholar have been associated with dilated cardiomyopathy, the TTN variant identified in our patient occurs in the M band of TTN. Variants in this region are not definitively known to be associated with cardiac disease. It is believed that all individuals have rare missense variants in this gene.14Norton N. Li D. Rampersaud E. et al.Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy.Circ Cardiovasc Genet. 2013; 6: 144-153Crossref PubMed Scopus (75) Google Scholar Although our patient did have evidence of left ventricular systolic dysfunction immediately after her arrest, she demonstrated quick recovery. It was interpreted that the TTN and RYR2 variants were unlikely to be related to the patient’s clinical phenotype. The KCNQ1 variant, however, is a novel variant, absent from population databases, occurring at the same position as a variant previously reported in association with SQTS, p.Phe279Ile. The Phe279 residue is highly conserved across species. It has been demonstrated that this position is of functional importance, as the KCNQ1 Phe279 residue collides with Phe232 in the presence of KCNE1 and hinders the KCNQ1 channel from opening.6Nakajo K. Kubo Y. Steric hindrance between S4 and S5 of the KCNQ1/KCNE1 channel hampers pore opening.Nat Commun. 2014; 5: 4100Crossref PubMed Scopus (22) Google Scholar Our patient’s variant, p.Phe279Cys, has been shown to impact KCNQ1 functionality by decreasing the membrane potential—an effect that is enhanced in the presence of KCNE1.6Nakajo K. Kubo Y. Steric hindrance between S4 and S5 of the KCNQ1/KCNE1 channel hampers pore opening.Nat Commun. 2014; 5: 4100Crossref PubMed Scopus (22) Google Scholar The authors who reported the p.Phe279Ile variant demonstrated that this variant resulted in altered assembly with KCNE1, and induced gain-of-function of slow delayed rectifier potassium channels.7Moreno C. Oliveras A. de la Cruz A. et al.A new KCNQ1 mutation at the S5 segment that impairs its association with KCNE1 is responsible for short QT syndrome.Cardiovasc Res. 2015; 107: 613-623Crossref PubMed Google Scholar SQTS remains a rare cardiac channelopathy associated with sudden cardiac death. Given the small number of patients, there continues to be investigation into the clinical and genetic associations with the diagnosis. Our patient fulfills diagnostic criteria for SQTS based on the 2013 HRS/EHRA/APHRS consensus statement and Gollob’s proposed SQTS diagnostic criteria, and her genetic testing shows a novel variant in a gene known to be associated with SQTS. This variant occurs at a position demonstrated to have relevance to slow delayed potassium channel function, occurs at a position where another missense variant has been published in association with SQTS with supportive functional data, and is consistent with both our patient’s and patient’s mother’s phenotype. This variant is also absent from population databases. As such, though it is currently classified by the performing laboratory as a variant of uncertain significance, we assess that there is strong evidence suggesting that this variant is likely disease-causing.Key Teaching Points•Short QT syndrome remains a rare and fairly recently discovered cardiac channelopathy, and there are still a substantial number of patients for whom no causative genetic mutation is identified. Owing to the still relatively small patient cohort, it is important to investigate new, potentially pathologic variants to contribute to the understanding of the disease.•In cardiac channelopathies, variants of uncertain significance (VUS) should be interpreted in close conjunction with the clinical context. If there is sufficient clinical suspicion of a given disease, a genetic test result alone should not be the decisive diagnostic factor. Likewise, a genetic variant alone should typically not be used to confirm a diagnosis in the absence of sufficient clinical evidence. Depending on the index of clinical suspicion, the potential clinical significance of a VUS may require further investigation, including family and functional studies when possible.•Short QT syndrome remains a rare diagnosis with continued investigation into the clinical and genetic associations. Given the relatively small cohort, patients with suspected short QT syndrome should undergo rigorous clinical and genetic evaluation to help refine diagnostic criteria.