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1.
Sorbonne Université- DMU BioGem-Unité Fonctionnelle de Cardiogénétique et Myogénétique Moléculaire et cellulaire, Service de Biochimie Métabolique, APHP-Hôpital Universitaire Pitié Salpêtrière, Paris, France; INSERM UMRS1166 Équipe 1, ICAN Institute, Paris, France; Université Paris Cité, UFR de Pharmacie, 4 av de l'observatoire, 75006 Paris, France.
Authors
Ader F
1
(1 author)
2.
M3C-Necker, Cardiologie Congénitale et Pédiatrique, APHP- Hôpital Universitaire Necker-Enfants malades, Paris, France.
Authors
Derridj N
2
Khraiche D
2
(2 authors)
3.
CHU de Rouen, Service de Génétique, Rouen, France.
Authors
Brehin AC
3
(1 author)
4.
CHU de Lille, Service de Cardiologie Pédiatrique, Lille, France.
Authors
Domanski O
4
Baudelet JB
4
Gras P
4
(3 authors)
5.
CHU de Nantes, Service de Cardiologie Pédiatrique, Nantes, France.
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Abstract
Background
There are limited data that can explain the earlier penetrance and the different expressivity of pediatric cardiomyopathy (pCM) compared to adult-onset cardiomyopathy (aCM). In addition, the relationship between genotype and pCM results is poorly described.
Objective
We compared the genotypes between a cohort of aCM and a cohort of pCM to propose hypotheses on the earlier penetrance and expressivity of pCM. Finally, we report how genetic testing was used to guide genetic counseling in pCM.
Methods
253 pCM (<18 years old) and 1466 aCM patients were sequenced on a panel of 67 cardiomyopathy genes. Risk factors for death and heart transplantation were analyzed.
Results
In pCM, the variant of interest (VOI) yield was 53.7 % including 24.2 % carrying two VOI. De novo variants represented 11 % of VOI in pCM and 50 % in restrictive pCM. An age at diagnosis younger than 1 year (HR = 2.07, p = 0.029), restrictive phenotype (HR = 2.87, p = 0.03) and the presence of two VOI (HR = 2.97, p = 0.001) were independent risk factors for death or heart transplantation. In comparison with aCM, pCM patients harbored more frequently two VOI (p = 0.02), or de novo variants (p = 4.10-13). In addition, the distribution of VOI was different in aCM and pCM. Genotyping of pCM improved genetic counseling in families and led to ten prenatal-diagnosis.
Conclusions
Genetic testing provides clues for earlier penetrance of pCM. The presence of two VOI in children with CM is a risk factor for severe and early cardiac events.