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Novel trans-2,3-enoyl-CoA reductase–like variant associated with catecholaminergic polymorphic ventricular tachycardia type 3

  • Author Footnotes
    1 Drs Assaf and Charafeddine have contributed equally to this work and share first authorship.
    Fatme Charafeddine
    Footnotes
    1 Drs Assaf and Charafeddine have contributed equally to this work and share first authorship.
    Affiliations
    Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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  • Author Footnotes
    1 Drs Assaf and Charafeddine have contributed equally to this work and share first authorship.
    Nada Assaf
    Footnotes
    1 Drs Assaf and Charafeddine have contributed equally to this work and share first authorship.
    Affiliations
    Department of Pathology and Lab Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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  • Ali Ismail
    Affiliations
    Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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  • Ziad Bulbul
    Correspondence
    Address reprint requests and correspondence: Dr Ziad Bulbul, American University of Beirut Medical Center, Riad El Solh, Beirut 1107 2020, Beirut, Lebanon.
    Affiliations
    Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon
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  • Author Footnotes
    1 Drs Assaf and Charafeddine have contributed equally to this work and share first authorship.
Open AccessPublished:December 20, 2022DOI:https://doi.org/10.1016/j.hrcr.2022.12.013

      Keywords

      Introduction

      Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by polymorphic ventricular tachycardia, usually provoked by emotional stress or exercise, in the absence of any structural cardiac abnormality, and in the presence of often normal resting electrocardiogram (ECG).
      • Faggioni M.
      • Kryshtal D.O.
      • Knollmann B.C.
      Calsequestrin mutations and catecholaminergic polymorphic ventricular tachycardia.
      It is a highly lethal disease with an overall mortality of 30%–40% if left untreated.
      • Mohamed U.
      • Napolitano C.
      • Priori S.G.
      Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia.
      Studies have shown that almost 35% of affected individuals become symptomatic before the age of 10 and 75% before the age of 20 years.
      • Pflaumer A.
      • Davis A.M.
      Guidelines for the diagnosis and management of catecholaminergic polymorphic ventricular tachycardia.
      ,
      • Pflaumer A.
      • Wilde A.A.M.
      • Charafeddine F.
      • et al.
      50 Years of catecholaminergic polymorphic ventricular tachycardia (CPVT) - time to explore the dark side of the moon.
      The main culprits in CPVT are mutations in the cardiac ryanodine receptor gene (RYR2), which are inherited in an autosomal dominant pattern. However, recently, alterations in the trans-2,3-enoyl-CoA reductase–like (TECRL) gene have been implicated in the disease and associated with clinical features of both long QT syndrome (LQTS) and CPVT, classified under the category of atypical CPVT, or CPVT type 3.
      • Bhuiyan Z.A.
      • Hamdan M.A.
      • Shamsi E.T.
      • et al.
      A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22.
      Bhuiyan and colleagues
      • Bhuiyan Z.A.
      • Hamdan M.A.
      • Shamsi E.T.
      • et al.
      A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22.
      were the first to delineate the chromosomal location of the gene causing CPVT type 3 and described its novel autosomal recessive malignant phenotype in an inbred Arab family. The resultant protein belongs to the steroid 5-alpha reductase family and is predominantly expressed in the endoplasmic reticulum of myocardial cells. TECRL plays a key role in the intracellular calcium balance and homeostasis. It has been shown to regulate the activity of calsequestrin-2 (CASQ-2), ryanodine-receptor 2 (RYR2), and other cardiac channels.
      • Moscu-Gregor A.
      • Marschall C.
      • Müntjes C.
      • et al.
      Novel variants in TECRL cause recessive inherited CPVT type 3 with severe and variable clinical symptoms.
      An initial mechanistic study showed downregulation of RYR2 and CASQ-2 in some cell lines affected by TECRL abnormalities.
      • Webster G.
      • Aburawi E.H.
      • Chaix M.A.
      • et al.
      Life-threatening arrhythmias with autosomal recessive TECRL variants.
      ,
      • Devalla H.D.
      • Gélinas R.
      • Aburawi E.H.
      • et al.
      TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT.
      These cell lines also had smaller calcium transient amplitudes, slower decay, and elevated diastolic calcium. Stimulation by noradrenaline significantly increased the propensity for triggered activity based on delayed afterdepolarization in TECRLHom human induced pluripotent stem cell–derived cardiomyocytes.
      • Devalla H.D.
      • Gélinas R.
      • Aburawi E.H.
      • et al.
      TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT.
      To date, only 16 families have been described in the literature, 7 of which were recently reported in an international multicenter retrospective review. Countries of origin include Canada, Inner Mongolia, Bangladesh, Iraq, Sudan, and Turkey.
      • Webster G.
      • Aburawi E.H.
      • Chaix M.A.
      • et al.
      Life-threatening arrhythmias with autosomal recessive TECRL variants.
      ,
      • Xie L.
      • Hou C.
      • Jiang X.
      • et al.
      A compound heterozygosity of Tecrl gene confirmed in a catecholaminergic polymorphic ventricular tachycardia family.
      Reported phenotypes were notable for their clinical divergence with variable arrhythmia profile, often malignant, including those typical of long QT syndrome and CPVT.
      We herein report a novel frameshift mutation in the TECRL gene identified in 2 affected Lebanese siblings, in the context of a positive family history of sudden death in their 2 other siblings. This variant was detected in the homozygous state in the probands and in their consanguineous asymptomatic parents in heterozygosity.

      Case report

      Family history

      The oldest female member of the family, who was reportedly healthy, collapsed at the age of 16 years while climbing stairs and could not be resuscitated. Two years later, the youngest, a 5-year-old brother (known to have mild developmental delay), collapsed immediately after choking while eating, as he went flaccid without coughing or initiating any reflex. He regained pulse after defibrillation in the hospital, but sustained brain death and died 1 month later. Both children had normal cardiac examination on screening visit, having normal resting ECG and 2-D echocardiography.
      No molecular or tissue autopsy was done for any of the deceased victims.

      Clinical case review

      The siblings’ 13-year-old sister often reported nausea and dizziness when emotionally stressed, and during sports activity. However, she never lost consciousness or fainted either at rest or during exercise. The 9-year-old brother reported palpitations on exercise, but never fainted. Both patients showed mild QT prolongation at rest (QTcB: 0.47) that shortened during exercise, but they did manifest abnormal QT prolongation during the recovery period, with very peculiar abnormal T-wave morphology (flat and bifid with prominent u wave). Bidirectional ventricular ectopic beats, sometimes in couplets, did appear in both cases during the sprint phase of the exercise stress test and did resolve in the recovery stage (Figures 1 and 2).
      Figure thumbnail gr1
      Figure 1a: Boy’s resting 12-lead electrocardiogram. Sinus rhythm; mild QT prolongation; abnormal T wave with flat, bifid appearance; and prominent u waves. b: One bidirectional ventricular couplet on the sprint exercise stress test at peak exercise, for which the test was immediately terminated. c: QT dynamics in lead II during the recovery stage. Baseline: green curve, green arrow delineating end of T wave at baseline by tangent method. Recovery stage: black curve, black arrow delineating end of T wave at recovery by tangent method. In recovery, QT prolonged to a maximum value of QTc (B): 0.496.
      Figure thumbnail gr2ab
      Figure 2a: Sister’s resting 12-lead electrocardiogram. Sinus bradycardia with sinus arrhythmia. Abnormal T-wave morphology, with prominent u wave. Prolonged QTc at 0.47 (measured by tangent method excluding the u wave as shown by the double arrow). b: Sprint exercise stress test: (I) Isolated premature ventricular contractions (PVCs) during early sprint phase that happened more frequently, in trigeminy, followed by (II) bigeminy with bidirectional PVCs, for which (III) the test was immediately terminated. (IV) In immediate recovery, she did develop 23 PVCs, within 30 seconds, mostly in bigeminy pattern, with 3 sets of bidirectional PVCs, polymorphic with widened QRS duration. (V, VI) PVCs disappeared during the rest of recovery stage. In recovery, QT prolonged to a maximum value of QTc: 0.5, with more bifid T-wave appearance, sometimes with variable T-wave amplitude, and prominent u wave. c: QT dynamics in lead II during the recovery stage. Baseline: green curve, green arrow delineating end of T wave at baseline by tangent method. Recovery stage: black curve, black arrow delineating end of T wave at recovery by tangent method. In recovery, QT prolonged to a maximum value of QTc (B): 0.5.
      Figure thumbnail gr2bc
      Figure 2a: Sister’s resting 12-lead electrocardiogram. Sinus bradycardia with sinus arrhythmia. Abnormal T-wave morphology, with prominent u wave. Prolonged QTc at 0.47 (measured by tangent method excluding the u wave as shown by the double arrow). b: Sprint exercise stress test: (I) Isolated premature ventricular contractions (PVCs) during early sprint phase that happened more frequently, in trigeminy, followed by (II) bigeminy with bidirectional PVCs, for which (III) the test was immediately terminated. (IV) In immediate recovery, she did develop 23 PVCs, within 30 seconds, mostly in bigeminy pattern, with 3 sets of bidirectional PVCs, polymorphic with widened QRS duration. (V, VI) PVCs disappeared during the rest of recovery stage. In recovery, QT prolonged to a maximum value of QTc: 0.5, with more bifid T-wave appearance, sometimes with variable T-wave amplitude, and prominent u wave. c: QT dynamics in lead II during the recovery stage. Baseline: green curve, green arrow delineating end of T wave at baseline by tangent method. Recovery stage: black curve, black arrow delineating end of T wave at recovery by tangent method. In recovery, QT prolonged to a maximum value of QTc (B): 0.5.
      Both patients had a mild degree of bileaflet mitral valve prolapse with thickened leaflet tips and mild regurgitation on echocardiography, with preserved left atrial size and left ventricular function. Cardiac magnetic resonance imaging was negative for any underlying scar tissue or delayed enhancement.
      Patients were initially started on low-dose propranolol prior to their referral to our center. This treatment rationale was mainly due to the presence of the premature ventricular complexes (PVCs), thought to be originating from the right ventricular outflow tract, seen during exercise testing and Holter monitoring. A genetic workup was initiated. Whole exome sequencing, performed at Centogene laboratory (Rostock, Germany), revealed the presence of a homozygous variant of unknown significance in the TECRL gene in the peripheral blood of the 9-year-old boy. He was then referred to the pediatric electrophysiology service at the Children’s Heart Center at the American University of Beirut for further evaluation.
      Following the referral, he was diagnosed as having mixed clinical features of both LQTS and CPVT. We also did the same diagnostic workup in his sister and established the diagnosis for her as well.
      Segregation studies were performed and the novel TECRL variant was confirmed by Sanger sequencing. The affected sister was found to carry the homozygous c.742_758 del variant, resulting in a protein variant (p.Arg248Cysfs∗), while the consanguineous asymptomatic parents were heterozygote carriers.
      Both patients were switched to nadolol at a starting dose of 1 mg/kg/day. The sprint exercise stress test was repeated and continued to show evidence of PVCs on exercise. Flecainide was added as part of a dual therapy regimen, which completely suppressed the exercise-induced ventricular ectopy in both patients.
      Given the previously described highly malignant phenotype caused by pathogenic biallelic variants in the TECRL gene, and the overlapping features of long QT and CPVT, we opted to implant transvenous implantable cardioverter-defibrillators (ICDs) in both affected patients as part of our primary prevention approach, despite our consensual approach to avoid as much as possible the implantation of ICD in CPVT patients. However, we did make sure to lengthen the ventricular fibrillation detection rate and turn off anti-tachycardia pacing to minimize the risk of electrical storms in those patients.
      The importance of strict medication compliance was emphasized, along with the recommendation to avoid drugs that prolong the QT interval (list available on the website: crediblemeds.org) and to avoid competitive exercise and all other known triggers of ventricular tachycardia in CPVT. This includes cold water, swimming, severe electrolyte loss, sudden startling, and adrenaline.
      To date, 7 months into follow-up, both patients remain clinically well, with no events recorded, and free of ICD shocks. They remain free of symptoms and of any exercise-induced ventricular arrhythmias.

      Genetic evaluation and family screening approach

      As viewed on Alamut Visual (version 2.14), the detected variant (NM_001010874.4:c.742_758del; ClinVar Accession number: SCV001805856.1) results from a 17 bp deletion in exon 8 of the TECRL gene creating a shift in the reading frame starting at codon Arg248 (frameshift mutation). The new reading frame ends in a stop codon 8 positions downstream. Because loss of function is not a well-established mechanism for TECRL, the c.742_758del variant was classified by the referral lab as a variant of unknown pathogenicity (Class 3). However, the following criteria suggest the upgrade of this variant to likely pathogenic (Class 4) according to American College of Medical Genetics guidelines
      • Richards S.
      • Aziz N.
      • Bale S.
      • 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.
      :
      • Absence in general population databases (gnomAD, 1000 Genomes Project, and ExAC) (PM2)
      • Mutation causing a change in protein length owing to stop losses (PM4)
      • Segregation analysis revealing an autosomal recessive inheritance (PP1)
      • Genotype-phenotype correlation: pathogenic variants in the TECRL gene were previously reported to be associated with a mixed phenotype of long QT and CPVT (CPVT type 3) (PP4)
        • Devalla H.D.
        • Gélinas R.
        • Aburawi E.H.
        • et al.
        TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT.
        ,
        • Xie L.
        • Hou C.
        • Jiang X.
        • et al.
        A compound heterozygosity of Tecrl gene confirmed in a catecholaminergic polymorphic ventricular tachycardia family.
      Both consanguineous parents were found to be heterozygous for this TECRL variant. The mother showed normal cardiac evaluation in terms of ECG, echocardiography, and exercise stress test. The latter was done according to the Bruce protocol, during which she reached 92% of maximal heart rate, with no evidence of PVCs at maximal exercise and no abnormal QT prolongation in recovery. The father had normal resting ECG and echocardiography, but he developed 4 isolated monomorphic PVCs at maximal exercise of Bruce protocol (heart rate of 154 beats/min; 90% of target heart rate); ECG tracings of the PVCs were not provided to us, unfortunately. We have requested additional cardiac investigations from our adult colleagues, including but not limited to a sprint exercise stress test and Holter evaluation. At this stage, we need more data to draw any definitive conclusion about the cardiac phenotype in heterozygous state of TECRL, as it has not been described as abnormal in the literature so far
      • Webster G.
      • Aburawi E.H.
      • Chaix M.A.
      • et al.
      Life-threatening arrhythmias with autosomal recessive TECRL variants.
      ; however, we may be the first to point toward a potential positive link between the exercise-induced ectopy and heterozygous TECRL carriers similar to what has been reported in other calcium dysregulation disease states, such as CASQ2 mutations.
      • Ng K.
      • Titus E.
      • Lieve K.
      • et al.
      An international multicenter evaluation of inheritance patterns, arrhythmic risks, and underlying mechanisms of CASQ2-catecholaminergic polymorphic ventricular tachycardia.
      Significant endogamy was noticed within this family community (Figure 3) and genetic counseling was offered with emphasis on the mode of inheritance of autosomal recessive diseases and consanguinity. Genetic screening with cascade testing for the first-degree relatives who are at highest risk of having TECRL homozygous children was recommended.
      Figure thumbnail gr3
      Figure 3Extended family pedigree showing significant endogamy between relatives.

      Discussion and conclusion

      We aimed to present additional evidence in favor of the pathogenicity of the biallelic loss-of-function variants in the TECRL gene by presenting a novel mutation in a highly consanguineous Lebanese family. We also described our management approach, which further highlights the superiority of the dual therapy regimen in such patients, in particular the effect of the added flecainide in reducing exercise-induced ventricular ectopy. This comes in agreement with the in vitro evidence that supports the use of flecainide in patients with TECRL variants, by reducing the triggered activity based on delayed afterdepolarization.
      • Devalla H.D.
      • Gélinas R.
      • Aburawi E.H.
      • et al.
      TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT.
      The detection of a common cardiac structural abnormality in both patients carrying a homozygous TECRL mutation is unique to our case and has not yet been reported, to the best of our knowledge. This observation still needs to be further investigated, as it may or may not be related to the genetic mutation.
      We hope to encourage screening for TECRL variants when dealing with patients presenting with similar clinical phenotypes or showing evidence of exercise-induced ventricular arrhythmias or CPVT.
      Heterozygous carriers should be thoroughly investigated for any signs of exercise-induced ectopy, similar to what has been reported in other calcium dysregulation disease states.
      Based on our experience, and previous reports published in the literature, we call for including the TECRL gene in the commercially available next-generation sequencing panels for sudden death and LQTS/CPVT, similar to what has been implemented by the Department of Molecular Genetics at Martinsried, Germany.
      • Moscu-Gregor A.
      • Marschall C.
      • Müntjes C.
      • et al.
      Novel variants in TECRL cause recessive inherited CPVT type 3 with severe and variable clinical symptoms.
      Until achieved worldwide, we advise for actively looking for TECRL gene mutations whenever dealing with consanguineous families from the Greater Middle East area with a history of sudden death in the young. An active area for future research is to create additional induced pluripotent stem cell–derived-derived cardiac myocytes to test pharmaceutical therapies. This will guide in the delivery of individualized care, hence providing precision medicine.
      Key Teaching Points
      • Additional evidence is presented in favor of the pathogenicity of the biallelic loss-of-function variants in the TECRL gene causing CPVT type 3 through the description of a novel mutation in a consanguineous Lebanese family.
      • Flecainide addition to beta-blockers is effective in reducing exercise-induced ventricular ectopy.
      • The TECRL gene should be included in the next-generation sequencing sudden death panels as well in the LQTS and CPVT screening panels that are commercially available worldwide.

      Acknowledgments

      The authors thank Professor Arthur A.M. Wilde from the Academic Medical Center, Amsterdam, Dr Andrew P. Landstrom from Duke University Medical Center, and Professor Silvia G. Priori from the Scientific Clinical Institute of Maugeri, Italy, for providing their expert clinical and genetic inputs during the case management.

      References

        • Faggioni M.
        • Kryshtal D.O.
        • Knollmann B.C.
        Calsequestrin mutations and catecholaminergic polymorphic ventricular tachycardia.
        Pediatr Cardiol. 2012; 33: 959-967
        • Mohamed U.
        • Napolitano C.
        • Priori S.G.
        Molecular and electrophysiological bases of catecholaminergic polymorphic ventricular tachycardia.
        J Cardiovasc Electrophysiol. 2007; 18: 791-797
        • Pflaumer A.
        • Davis A.M.
        Guidelines for the diagnosis and management of catecholaminergic polymorphic ventricular tachycardia.
        Heart Lung Circ. 2012; 21: 96-100
        • Pflaumer A.
        • Wilde A.A.M.
        • Charafeddine F.
        • et al.
        50 Years of catecholaminergic polymorphic ventricular tachycardia (CPVT) - time to explore the dark side of the moon.
        Heart Lung Circ. 2020; 29: 520-528
        • Bhuiyan Z.A.
        • Hamdan M.A.
        • Shamsi E.T.
        • et al.
        A novel early onset lethal form of catecholaminergic polymorphic ventricular tachycardia maps to chromosome 7p14-p22.
        J Cardiovasc Electrophysiol. 2007; 18: 1060-1066
        • Moscu-Gregor A.
        • Marschall C.
        • Müntjes C.
        • et al.
        Novel variants in TECRL cause recessive inherited CPVT type 3 with severe and variable clinical symptoms.
        J Cardiovasc Electrophysiol. 2020; 31: 1527-1535
        • Webster G.
        • Aburawi E.H.
        • Chaix M.A.
        • et al.
        Life-threatening arrhythmias with autosomal recessive TECRL variants.
        Europace. 2021; 23: 781-788
        • Devalla H.D.
        • Gélinas R.
        • Aburawi E.H.
        • et al.
        TECRL, a new life-threatening inherited arrhythmia gene associated with overlapping clinical features of both LQTS and CPVT.
        EMBO Mol Med. 2016; 8: 1390-1408
        • Xie L.
        • Hou C.
        • Jiang X.
        • et al.
        A compound heterozygosity of Tecrl gene confirmed in a catecholaminergic polymorphic ventricular tachycardia family.
        Eur J Med Genet. 2019; 62103631
        • Richards S.
        • Aziz N.
        • Bale S.
        • 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
        • Ng K.
        • Titus E.
        • Lieve K.
        • et al.
        An international multicenter evaluation of inheritance patterns, arrhythmic risks, and underlying mechanisms of CASQ2-catecholaminergic polymorphic ventricular tachycardia.
        Circulation. 2020; 10: 932-947