Advertisement
Canadian Journal of Cardiology

Impact of a 22q11.2 Microdeletion on Adult All-Cause Mortality in Tetralogy of Fallot Patients

  • Spencer van Mil
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    The Dalglish Family 22q Clinic, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Tracy Heung
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    The Dalglish Family 22q Clinic, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Sarah Malecki
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    The Dalglish Family 22q Clinic, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Lily Van
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    The Dalglish Family 22q Clinic, University Health Network, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
  • Janis Chang
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    The Dalglish Family 22q Clinic, University Health Network, Toronto, Ontario, Canada
    Search for articles by this author
  • Elemi Breetvelt
    Affiliations
    Department of Psychiatry, The Hospital for Sick Children, Toronto, Ontario, Canada
    Search for articles by this author
  • Rachel Wald
    Affiliations
    Toronto Congenital Cardiac Centre for Adults, Division of Cardiology at the Peter Munk Cardiac Centre, Department of Medicine, University Health Network; and University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
  • Erwin Oechslin
    Affiliations
    The Dalglish Family 22q Clinic, University Health Network, Toronto, Ontario, Canada

    Toronto Congenital Cardiac Centre for Adults, Division of Cardiology at the Peter Munk Cardiac Centre, Department of Medicine, University Health Network; and University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
  • Candice Silversides
    Affiliations
    The Dalglish Family 22q Clinic, University Health Network, Toronto, Ontario, Canada

    Toronto Congenital Cardiac Centre for Adults, Division of Cardiology at the Peter Munk Cardiac Centre, Department of Medicine, University Health Network; and University of Toronto, Toronto, Ontario, Canada
    Search for articles by this author
  • Anne S. Bassett
    Correspondence
    Corresponding author: Dr Anne S. Bassett, The Dalglish Family 22q Clinic, 8NU-802, 200 Elizabeth St, Toronto General Hospital, Toronto, Ontario M5G 2C4, Canada. Tel.: +1-416-340-5145; fax: +1-416-340-5004.
    Affiliations
    Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, Ontario, Canada

    The Dalglish Family 22q Clinic, University Health Network, Toronto, Ontario, Canada

    Department of Psychiatry, University of Toronto, Toronto, Ontario, Canada

    Toronto Congenital Cardiac Centre for Adults, Division of Cardiology at the Peter Munk Cardiac Centre, Department of Medicine, University Health Network; and University of Toronto, Toronto, Ontario, Canada

    Toronto General Hospital Research Institute and Campbell Family Mental Health Research Institute, Toronto, Ontario, Canada
    Search for articles by this author
Published:April 26, 2020DOI:https://doi.org/10.1016/j.cjca.2020.04.019

      Abstract

      Background

      Because of the importance of identifying factors that affect late outcomes in the increasing population of those with tetralogy of Fallot (TOF), we aimed to determine the effect of a 22q11.2 microdeletion on adult mortality, while accounting for pulmonary atresia, known to be enriched in 22q11.2 deletion syndrome (22q11.2DS).

      Methods

      We studied 612 individuals with TOF recruited as adults at a single centre, 80 (13.1%) with molecularly confirmed 22q11.2 deletions and 532 without 22q11.2DS, followed for a total of 5961.3 person-years. Using a case-control design, Cox proportional hazard regression and Kaplan-Meier curves, we evaluated the effect of a 22q11.2 deletion on mortality and survival.

      Results

      All-cause mortality was 1.87% per person-year in the 22q11.2DS-TOF group and 0.80% in the other-TOF group. The presence of a 22q11.2 microdeletion was a significant predictor of adult mortality in TOF (hazard ratio, 5.00; P < 0.0001), after accounting for pulmonary atresia (hazard ratio, 2.71; P = 0.0106) and other factors. Overall, individuals with 22q11.2DS died on average 17.7 years earlier (P = 0.0055) than others with TOF, predominantly of cardiovascular causes, with proportionately more sudden cardiac deaths in those with 22q11.2DS-TOF (n = 5 [38.5%] vs n = 5 [11.9%], other-TOF; P = 0.0447). Kaplan-Meier curves showed reduced survival for those with 22q11.2DS (P < 0.0001); probability of survival to age 45 years, without pulmonary atresia, was 72% (22q11.2DS-TOF) and 98% (other-TOF).

      Conclusions

      The results suggest that the 22q11.2 deletion significantly contributes to premature mortality in adults with TOF, mediated only in part by greater anatomic complexity. The interpretation of late outcome data in TOF will likely benefit from further genetic subtyping.

      Résumé

      Contexte

      Comme il importe de déterminer les facteurs susceptibles d’influer sur les résultats à long terme au sein de la population de plus en plus importante de patients présentant une tétralogie de Fallot (TF), nous avons tenté d’évaluer l’effet de la microdélétion 22q11.2 sur la mortalité chez l’adulte, en tenant compte de la présence d’une atrésie pulmonaire, fréquemment associée au syndrome de délétion 22q11.2 (SD22q11.2).

      Méthodologie

      Nous avons étudié les cas des 612 patients présentant une TF recrutés à l’âge adulte dans un même centre. La présence d’une délétion 22q11.2 a été confirmée par analyse moléculaire chez 80 (13,1 %) d’entre eux; les 532 autres patients n’étaient pas porteurs d’une telle délétion. Les sujets ont fait l’objet d’un suivi d’une durée totale de 5961,3 années-personnes. Dans le cadre de cette étude cas-témoin, nous avons évalué l’effet d’une délétion 22q11.2 sur la mortalité et la survie à l’aide d’un modèle de régression à risques proportionnels de Cox et de courbes de Kaplan-Meier.

      Résultats

      La mortalité toutes causes confondues s’établissait à 1,87 % par année-personne dans le groupe TF-SD22q11.2 et à 0,80 % dans le groupe TF-autre. La présence d’une microdélétion 22q11.2 s’est révélée être un important facteur de prédiction de la mortalité à l’âge adulte chez les patients atteints de TF (rapport des risques instantanés [RRI], 5,00; p < 0,0001), après correction pour tenir compte de la présence d’une atrésie pulmonaire (RRI, 2,71; p = 0,0106) et d’autres facteurs. Dans l’ensemble, le décès survenait 17,7 ans plus tôt en moyenne (p = 0,0055) dans le groupe TF-SD22q11.2 que dans le groupe TF-autre, et était principalement attribuable à des causes cardiovasculaires, les cas de mort cardiaque subite étant proportionnellement plus fréquents dans le groupe TF-SD22q11.2 (n = 5 [38,5 %]) vs n = 5 [11,9 %] dans le groupe TF-autre; p = 0,0447). Les courbes de Kaplan-Meier ont montré une diminution de la survie dans les cas de SD22q11.2 (p < 0,0001); les probabilités de survie jusqu’à l’âge de 45 ans en l’absence d’atrésie pulmonaire étaient de 72 % (groupe TF-SD22q11.2) et de 98 % (groupe TF-autre).

      Conclusions

      Les résultats semblent indiquer que la présence d’une délétion 22q11.2 contribue de manière significative à la mortalité prématurée chez les adultes présentant une TF, qui serait donc attribuable en partie seulement à une complexité anatomique accrue. Un sous-typage génétique plus poussé permettrait probablement d’approfondir l’interprétation des données sur les issues à long terme chez les sujets présentant une TF.
      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Canadian Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Reller M.D.
        • Strickland M.J.
        • Riehle-Colarusso T.
        • Mahle W.T.
        • Correa A.
        Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005.
        J Pediatr. 2008; 153: 807-813
        • Marelli A.J.
        • Ionescu-Ittu R.
        • Mackie A.S.
        • et al.
        Lifetime prevalence of congenital heart disease in the general population from 2000 to 2010.
        Circulation. 2014; 130: 749-756
        • Diller G.P.
        • Kempny A.
        • Alonso-Gonzalez R.
        • et al.
        Survival prospects and circumstances of death in contemporary adult congenital heart disease patients under follow-up at a large tertiary centre.
        Circulation. 2015; 132: 2118-2125
        • Stout K.K.
        • Daniels C.J.
        • Aboulhosn J.A.
        • et al.
        2018 AHA/ACC guideline for the management of adults with congenital heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.
        Circulation. 2019; 139: e637-e697
        • Smith C.A.
        • McCracken C.
        • Thomas A.S.
        • et al.
        Long-term outcomes of tetralogy of Fallot: a study from the pediatric cardiac care consortium.
        JAMA Cardiol. 2019; 4: 34-41
        • Valente A.M.
        • Gauvreau K.
        • Assenza G.E.
        • et al.
        Contemporary predictors of death and sustained ventricular tachycardia in patients with repaired tetralogy of Fallot enrolled in the INDICATOR cohort.
        Heart. 2014; 100: 247-253
        • Oliver J.M.
        • Gallego P.
        • Gonzalez A.E.
        • et al.
        Risk factors for excess mortality in adults with congenital heart diseases.
        Eur Heart J. 2017; 38: 1233-1241
        • Peyvandi S.
        • Lupo P.J.
        • Garbarini J.
        • et al.
        22q11.2 deletions in patients with conotruncal defects: data from 1,610 consecutive cases.
        Pediatr Cardiol. 2013; 34: 1687-1694
        • Van L.
        • Heung T.
        • Graffi J.
        • et al.
        All-cause mortality and survival in adults with 22q11.2 deletion syndrome.
        Genet Med. 2019; 21: 2328-2335
        • Silversides C.K.
        • Lionel A.C.
        • Costain G.
        • et al.
        Rare copy number variations in adults with tetralogy of Fallot implicate novel risk gene pathways.
        PLoS Genet. 2012; 8e1002843
        • Reuter M.S.
        • Jobling R.
        • Chaturvedi R.R.
        • et al.
        Haploinsufficiency of vascular endothelial growth factor related signaling genes is associated with tetralogy of Fallot.
        Genet Med. 2019; 21: 1001-1007
        • McDonald-McGinn D.M.
        • Sullivan K.E.
        • Marino B.
        • et al.
        22q11.2 deletion syndrome.
        Nat Rev Dis Primers. 2015; 1: 15071
        • Guna A.
        • Butcher N.J.
        • Bassett A.S.
        Comparative mapping of the 22q11.2 deletion region and the potential of simple model organisms.
        J Neurodev Disord. 2015; 7: 18
        • Fung W.L.
        • Chow E.W.
        • Webb G.D.
        • Gatzoulis M.A.
        • Bassett A.S.
        Extracardiac features predicting 22q11.2 deletion syndrome in adult congenital heart disease.
        Int J Cardiol. 2008; 131: 51-58
        • Raissadati A.
        • Nieminen H.
        • Haukka J.
        • Sairanen H.
        • Jokinen E.
        Late causes of death after pediatric cardiac surgery: a 60-year population-based study.
        J Am Coll Cardiol. 2016; 68: 487-498
        • Engelings C.C.
        • Helm P.C.
        • Abdul-Khaliq H.
        • et al.
        Cause of death in adults with congenital heart disease - an analysis of the German National Register for Congenital Heart Defects.
        Int J Cardiol. 2016; 211: 31-36
        • Hickey E.J.
        • Veldtman G.
        • Bradley T.J.
        • et al.
        Late risk of outcomes for adults with repaired tetralogy of Fallot from an inception cohort spanning four decades.
        Eur J Cardiothorac Surg. 2009; 35: 156-164
        • Michielon G.
        • Marino B.
        • Oricchio G.
        • et al.
        Impact of DEL22q11, trisomy 21, and other genetic syndromes on surgical outcome of conotruncal heart defects.
        J Thorac Cardiovasc Surg. 2009; 138: 565-570
        • Alsoufi B.
        • McCracken C.
        • Shashidharan S.
        • et al.
        The impact of 22q11.2 deletion syndrome on surgical repair outcomes of conotruncal cardiac anomalies.
        Ann Thorac Surg. 2017; 104: 1597-1604
        • McDonald R.
        • Dodgen A.
        • Goyal S.
        • et al.
        Impact of 22q11.2 deletion on the postoperative course of children after cardiac surgery.
        Pediatr Cardiol. 2013; 34: 341-347
        • Babliak O.D.
        • Mykychak Y.B.
        • Motrechko O.O.
        • Yemets I.M.
        Surgical treatment of pulmonary atresia with major aortopulmonary collateral arteries in 83 consecutive patients.
        Eur J Cardiothorac Surg. 2017; 52: 96-104
        • Mahle W.T.
        • Crisalli J.
        • Coleman K.
        • et al.
        Deletion of chromosome 22q11.2 and outcome in patients with pulmonary atresia and ventricular septal defect.
        Ann Thorac Surg. 2003; 76: 567-571
        • Kauw D.
        • Woudstra O.I.
        • van Engelen K.
        • et al.
        22q11.2 deletion syndrome is associated with increased mortality in adults with tetralogy of Fallot and pulmonary atresia with ventricular septal defect.
        Int J Cardiol. 2020; 306: 56-60
        • Kirklin J.W.
        • Blackstone E.H.
        • Shimazaki Y.
        • et al.
        Survival, functional status, and reoperations after repair of tetralogy of Fallot with pulmonary atresia.
        J Thorac Cardiovasc Surg. 1988; 96: 102-116
        • Momma K.
        Cardiovascular anomalies associated with chromosome 22q11.2 deletion syndrome.
        Am J Cardiol. 2010; 105: 1617-1624
        • van Engelen K.
        • Topf A.
        • Keavney B.D.
        • et al.
        22q11.2 deletion syndrome is under-recognised in adult patients with tetralogy of Fallot and pulmonary atresia.
        Heart. 2010; 96: 621-624
        • Wu M.H.
        • Lu C.W.
        • Chen H.C.
        • Kao F.Y.
        • Huang S.K.
        Adult congenital heart disease in a nationwide population 2000-2014: epidemiological trends, arrhythmia, and standardized mortality ratio.
        J Am Heart Assoc. 2018; 7e007907
        • Jernigan E.G.
        • Strassle P.D.
        • Stebbins R.C.
        • Meyer R.E.
        • Nelson J.S.
        Effect of concomitant birth defects and genetic anomalies on infant mortality in tetralogy of Fallot.
        Birth Defects Res. 2017; 109: 1154-1165
        • Malecki S.L.
        • Van Mil S.
        • Graffi J.
        • et al.
        A genetic model for multimorbidity in young adults.
        Genet Med. 2020; 22: 132-141

      Linked Article

      • Do These Genes Make My Heart Look Fat? Why Molecular Changes Matter in Congenital Heart Disease
        Canadian Journal of CardiologyVol. 36Issue 7
        • Preview
          In recent years, molecular testing in the medical world has exploded in popularity, mainly due to advances in the diagnosis and treatment of cancer and the pursuit of individualized medicine. Meanwhile, non-neoplastic fields seem to have lagged behind when it comes to harnessing the power of the genome at the bedside. This may be because the molecular landscape of non-neoplastic disease is often highly complex, with increased influence of environmental factors and frequent involvement of multiple genes.
        • Full-Text
        • PDF