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Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension

Background: Paediatric-onset idiopathic/hereditary pulmonary arterial hypertension (IPAH/HPAH) is partially linked to genetic factors that may also affect treatment response and outcome. The relation between clinical characteristics and pathogenicity of gene variants in childhood IPAH/HPAH is still...

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Autores principales: Xu, Zhuoyuan, Zhang, Hongsheng, Zhang, Chen, Li, Qiangqiang, Gu, Hong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9783670/
https://www.ncbi.nlm.nih.gov/pubmed/36555947
http://dx.doi.org/10.3390/jcm11247331
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author Xu, Zhuoyuan
Zhang, Hongsheng
Zhang, Chen
Li, Qiangqiang
Gu, Hong
author_facet Xu, Zhuoyuan
Zhang, Hongsheng
Zhang, Chen
Li, Qiangqiang
Gu, Hong
author_sort Xu, Zhuoyuan
collection PubMed
description Background: Paediatric-onset idiopathic/hereditary pulmonary arterial hypertension (IPAH/HPAH) is partially linked to genetic factors that may also affect treatment response and outcome. The relation between clinical characteristics and pathogenicity of gene variants in childhood IPAH/HPAH is still not well understood. Methods: We retrospectively analyzed IPAH/HPAH paediatric patients aged between 3 months and 18 years under follow-up at a large tertiary referral center. Whole-exome sequencing focused on PAH high-risk genes was performed in all patients. Pathogenicity grading of gene variant sites was assessed using ClinVar and population frequencies. The association between gene variants and death was studied using Cox proportional multivariate models. Results: Overall, 129 patients (54.3% females; 91.5% on PAH therapy) with a median age at diagnosis of 6.8 (IQR 3.4–10.7) years were included. A relevant PAH gene variant was detected in 95 patients (73.6%). The most common variants were in the BMPR2 (n = 43, 3%) gene. Over a median follow-up period of 27.6 months, 26 children died. The presence of a likely pathogenic genetic variant was significantly associated with survival (HR: 3.56, p = 0.005) on multivariable Cox analysis. The number of PAH-specific drugs at presentation was associated with better survival in the cohort with pathogenic variants (p = 0.02). Conclusions: Pathogenic/likely pathogenic genetic variants are prevalent in children with PAH and are related to a worse prognosis irrespective of other recognized risk factors in this population. Combination PAH therapy was associated with superior prognosis in children with pathogenic variants or BMPR2 variants. Therefore, proactive medical therapy should be employed in this population.
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spelling pubmed-97836702022-12-24 Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension Xu, Zhuoyuan Zhang, Hongsheng Zhang, Chen Li, Qiangqiang Gu, Hong J Clin Med Article Background: Paediatric-onset idiopathic/hereditary pulmonary arterial hypertension (IPAH/HPAH) is partially linked to genetic factors that may also affect treatment response and outcome. The relation between clinical characteristics and pathogenicity of gene variants in childhood IPAH/HPAH is still not well understood. Methods: We retrospectively analyzed IPAH/HPAH paediatric patients aged between 3 months and 18 years under follow-up at a large tertiary referral center. Whole-exome sequencing focused on PAH high-risk genes was performed in all patients. Pathogenicity grading of gene variant sites was assessed using ClinVar and population frequencies. The association between gene variants and death was studied using Cox proportional multivariate models. Results: Overall, 129 patients (54.3% females; 91.5% on PAH therapy) with a median age at diagnosis of 6.8 (IQR 3.4–10.7) years were included. A relevant PAH gene variant was detected in 95 patients (73.6%). The most common variants were in the BMPR2 (n = 43, 3%) gene. Over a median follow-up period of 27.6 months, 26 children died. The presence of a likely pathogenic genetic variant was significantly associated with survival (HR: 3.56, p = 0.005) on multivariable Cox analysis. The number of PAH-specific drugs at presentation was associated with better survival in the cohort with pathogenic variants (p = 0.02). Conclusions: Pathogenic/likely pathogenic genetic variants are prevalent in children with PAH and are related to a worse prognosis irrespective of other recognized risk factors in this population. Combination PAH therapy was associated with superior prognosis in children with pathogenic variants or BMPR2 variants. Therefore, proactive medical therapy should be employed in this population. MDPI 2022-12-09 /pmc/articles/PMC9783670/ /pubmed/36555947 http://dx.doi.org/10.3390/jcm11247331 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Xu, Zhuoyuan
Zhang, Hongsheng
Zhang, Chen
Li, Qiangqiang
Gu, Hong
Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension
title Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension
title_full Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension
title_fullStr Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension
title_full_unstemmed Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension
title_short Association between Genotype, Presentation, and Outcome in Childhood Idiopathic and Hereditary Pulmonary Arterial Hypertension
title_sort association between genotype, presentation, and outcome in childhood idiopathic and hereditary pulmonary arterial hypertension
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9783670/
https://www.ncbi.nlm.nih.gov/pubmed/36555947
http://dx.doi.org/10.3390/jcm11247331
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