title: Genetic analyses in a cohort of children with pulmonary hypertension.
abstract: The prevalence of germline mutations in paediatric pulmonary hypertension (PH) is poorly documented. The objective of this study was to determine the mutation frequency in PH genes in a paediatric cohort and describe the clinical characteristics of mutation carriers.The study involved 66 index cases with PH: 35 children with idiopathic pulmonary arterial hypertension (IPAH); five children with familial PAH (FPAH); three children with pulmonary veno-occlusive disease (PVOD); and 23 children with PAH associated with congenital heart disease (APAH-CHD).No mutations were found in the 23 children with APAH-CHD. In the 40 children with IPAH or FPAH, 12 mutations were found: five on BMPR2; four on ACVRL1; and three on TBX4. In the three PVOD cases, two carried the EIF2AK4 mutation. Mutation carriers had a more severe disease at diagnosis and more aggressive first-line therapy was required. The three patients with PVOD had a very severe disease at diagnosis and required a lung transplantation.The genetic architecture of paediatric PAH is enriched in ACVRL1 and TBX4 mutations compared to adult PAH, but further studies are required to confirm these results. Childhood-onset PAH in children carrying a mutation in one of the genes tested has a more severe presentation at diagnosis but a similar outcome to that observed in non-carriers.
authors: Université Paris Descartes, Sorbonne Paris Cité, Paris, France M3C-Unité Médico-Chirugicale de Cardiologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France marilyne.levy@ue3c.fr.
authors: Marilyne
authors: M
authors: Levy
authors: Genetics Dept, GH Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 1166-ICAN, Paris, France ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors: Mélanie
authors: M
authors: Eyries
authors: Université Paris Descartes, Sorbonne Paris Cité, Paris, France M3C-Unité Médico-Chirugicale de Cardiologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors: Isabelle
authors: I
authors: Szezepanski
authors: Université Paris Descartes, Sorbonne Paris Cité, Paris, France M3C-Unité Médico-Chirugicale de Cardiologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors: Magalie
authors: M
authors: Ladouceur
authors: Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 1166-ICAN, Paris, France ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors: Sophie
authors: S
authors: Nadaud
authors: Université Paris Descartes, Sorbonne Paris Cité, Paris, France M3C-Unité Médico-Chirugicale de Cardiologie Pédiatrique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France.
authors: Damien
authors: D
authors: Bonnet
authors: Genetics Dept, GH Pitié-Salpêtrière, Assistance Publique Hôpitaux de Paris, Paris, France Sorbonne Universités, UPMC Univ Paris 06, INSERM, UMR_S 1166-ICAN, Paris, France ICAN Institute for Cardiometabolism and Nutrition, Paris, France.
authors: Florent
authors: F
authors: Soubrier
mesh_terms: D030301:Activin Receptors, Type II / Q000235:genetics; D000293:Adolescent; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D065627:Familial Primary Pulmonary Hypertension / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006330:Heart Defects, Congenital / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D006439:Hemodynamics; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011668:Pulmonary Veno-Occlusive Disease / Q000150:complications / Q000175:diagnosis / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D020825:T-Box Domain Proteins; C491193:TBX4 protein, human; C425364:ACVRL1 protein, human; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II