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.
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Article info
Publication history
Published online: April 26, 2020
Accepted:
April 20,
2020
Received:
March 7,
2020
Footnotes
See editorial by Armstrong and Seidman, pages 997–999 of this issue.
See page 1097 for disclosure information.
Identification
Copyright
Crown Copyright © 2020 Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society. All rights reserved.
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