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Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing

Pulmonary atresia (PA) is a severe cyanotic congenital heart disease. Although some genetic mutations have been described to be associated with PA, the knowledge of pathogenesis is insufficient. The aim of this research was to use whole-exome sequencing (WES) to determine novel rare genetic variants...

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Autores principales: Xing, Junyue, Wang, Hongdan, Xie, Yuanyuan, Fan, Taibing, Cui, Cunying, Li, Yanan, Wang, Shuai, Gu, Weiyue, Wang, Chengzeng, Tang, Hao, Liu, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: De Gruyter 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10199322/
https://www.ncbi.nlm.nih.gov/pubmed/37215497
http://dx.doi.org/10.1515/biol-2022-0593
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author Xing, Junyue
Wang, Hongdan
Xie, Yuanyuan
Fan, Taibing
Cui, Cunying
Li, Yanan
Wang, Shuai
Gu, Weiyue
Wang, Chengzeng
Tang, Hao
Liu, Lin
author_facet Xing, Junyue
Wang, Hongdan
Xie, Yuanyuan
Fan, Taibing
Cui, Cunying
Li, Yanan
Wang, Shuai
Gu, Weiyue
Wang, Chengzeng
Tang, Hao
Liu, Lin
author_sort Xing, Junyue
collection PubMed
description Pulmonary atresia (PA) is a severe cyanotic congenital heart disease. Although some genetic mutations have been described to be associated with PA, the knowledge of pathogenesis is insufficient. The aim of this research was to use whole-exome sequencing (WES) to determine novel rare genetic variants in PA patients. We performed WES in 33 patients (27 patient–parent trios and 6 single probands) and 300 healthy control individuals. By applying an enhanced analytical framework to incorporate de novo and case–control rare variation, we identified 176 risk genes (100 de novo variants and 87 rare variants). Protein‒protein interaction (PPI) analysis and Genotype-Tissue Expression analysis revealed that 35 putative candidate genes had PPIs with known PA genes with high expression in the human heart. Expression quantitative trait loci analysis revealed that 27 genes that were identified as novel PA genes that could be affected by the surrounding single nucleotide polymorphism were screened. Furthermore, we screened rare damaging variants with a threshold of minor allele frequency at 0.5% in the ExAC_EAS and GnomAD_exome_EAS databases, and the deleteriousness was predicted by bioinformatics tools. For the first time, 18 rare variants in 11 new candidate genes have been identified that may play a role in the pathogenesis of PA. Our research provides new insights into the pathogenesis of PA and helps to identify the critical genes for PA.
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spelling pubmed-101993222023-05-21 Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing Xing, Junyue Wang, Hongdan Xie, Yuanyuan Fan, Taibing Cui, Cunying Li, Yanan Wang, Shuai Gu, Weiyue Wang, Chengzeng Tang, Hao Liu, Lin Open Life Sci Research Article Pulmonary atresia (PA) is a severe cyanotic congenital heart disease. Although some genetic mutations have been described to be associated with PA, the knowledge of pathogenesis is insufficient. The aim of this research was to use whole-exome sequencing (WES) to determine novel rare genetic variants in PA patients. We performed WES in 33 patients (27 patient–parent trios and 6 single probands) and 300 healthy control individuals. By applying an enhanced analytical framework to incorporate de novo and case–control rare variation, we identified 176 risk genes (100 de novo variants and 87 rare variants). Protein‒protein interaction (PPI) analysis and Genotype-Tissue Expression analysis revealed that 35 putative candidate genes had PPIs with known PA genes with high expression in the human heart. Expression quantitative trait loci analysis revealed that 27 genes that were identified as novel PA genes that could be affected by the surrounding single nucleotide polymorphism were screened. Furthermore, we screened rare damaging variants with a threshold of minor allele frequency at 0.5% in the ExAC_EAS and GnomAD_exome_EAS databases, and the deleteriousness was predicted by bioinformatics tools. For the first time, 18 rare variants in 11 new candidate genes have been identified that may play a role in the pathogenesis of PA. Our research provides new insights into the pathogenesis of PA and helps to identify the critical genes for PA. De Gruyter 2023-05-19 /pmc/articles/PMC10199322/ /pubmed/37215497 http://dx.doi.org/10.1515/biol-2022-0593 Text en © 2023 the author(s), published by De Gruyter https://creativecommons.org/licenses/by/4.0/This work is licensed under the Creative Commons Attribution 4.0 International License.
spellingShingle Research Article
Xing, Junyue
Wang, Hongdan
Xie, Yuanyuan
Fan, Taibing
Cui, Cunying
Li, Yanan
Wang, Shuai
Gu, Weiyue
Wang, Chengzeng
Tang, Hao
Liu, Lin
Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
title Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
title_full Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
title_fullStr Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
title_full_unstemmed Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
title_short Novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
title_sort novel rare genetic variants of familial and sporadic pulmonary atresia identified by whole-exome sequencing
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10199322/
https://www.ncbi.nlm.nih.gov/pubmed/37215497
http://dx.doi.org/10.1515/biol-2022-0593
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