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Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5

Renal hypodysplasia and cystic kidney diseases, the common non-glomerular causes of pediatric chronic kidney disease (CKD), are usually diagnosed by their clinical and imaging characteristics. The high degree of phenotypic heterogeneity, in both conditions, makes the correct final diagnosis dependen...

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Autores principales: Wang, Xiaoyuan, Xiao, Huijie, Yao, Yong, Xu, Ke, Liu, Xiaoyu, Su, Baige, Zhang, Hongwen, Guan, Na, Zhong, Xuhui, Zhang, Yanqin, Ding, Jie, Wang, Fang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290170/
https://www.ncbi.nlm.nih.gov/pubmed/34295353
http://dx.doi.org/10.3389/fgene.2021.697085
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author Wang, Xiaoyuan
Xiao, Huijie
Yao, Yong
Xu, Ke
Liu, Xiaoyu
Su, Baige
Zhang, Hongwen
Guan, Na
Zhong, Xuhui
Zhang, Yanqin
Ding, Jie
Wang, Fang
author_facet Wang, Xiaoyuan
Xiao, Huijie
Yao, Yong
Xu, Ke
Liu, Xiaoyu
Su, Baige
Zhang, Hongwen
Guan, Na
Zhong, Xuhui
Zhang, Yanqin
Ding, Jie
Wang, Fang
author_sort Wang, Xiaoyuan
collection PubMed
description Renal hypodysplasia and cystic kidney diseases, the common non-glomerular causes of pediatric chronic kidney disease (CKD), are usually diagnosed by their clinical and imaging characteristics. The high degree of phenotypic heterogeneity, in both conditions, makes the correct final diagnosis dependent on genetic testing. It is not clear, however, whether the frequencies of damaged alleles vary among different ethnicities in children with non-glomerular CKD, and this will influence the strategy used for genetic testing. In this study, 69 unrelated children (40 boys, 29 girls) of predominantly Han Chinese ethnicity with stage 2–5 non-glomerular CKD caused by suspected renal hypodysplasia or cystic kidney diseases were enrolled and assessed by molecular analysis using proband-only targeted exome sequencing and array-comparative genomic hybridization. Targeted exome sequencing discovered genetic etiologies in 33 patients (47.8%) covering 10 distinct genetic disorders. The clinical diagnoses in 13/48 patients (27.1%) with suspected renal hypodysplasia were confirmed, and two patients were reclassified carrying mutations in nephronophthisis (NPHP) genes. The clinical diagnoses in 16/20 patients (80%) with suspected cystic kidney diseases were confirmed, and one patient was reclassified as carrying a deletion in the hepatocyte nuclear factor-1-beta gene (HNF1B). The diagnosis of one patient with unknown non-glomerular disease was elucidated. No copy number variations were identified in the 20 patients with negative targeted exome sequencing results. NPHP genes were the most common disease-causing genes in the patients with disease onsets above 6 years of age (14/45, 31.1%). The children with stage 2 and 3 CKD at onset were found to carry causative mutations in paired box gene 2 (PAX2) and HNF1B gene (11/24, 45.8%), whereas those with stage 4 and 5 CKD mostly carried causative mutations in NPHP genes (19/45, 42.2%). The causative genes were not suspected by the kidney imaging patterns at disease onset. Thus, our data show that in Chinese children with non-glomerular renal dysfunction caused by renal hypodysplasia and cystic kidney diseases, the common causative genes vary with age and CKD stage at disease onset. These findings have the potential to improve management and genetic counseling of these diseases in clinical practice.
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spelling pubmed-82901702021-07-21 Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5 Wang, Xiaoyuan Xiao, Huijie Yao, Yong Xu, Ke Liu, Xiaoyu Su, Baige Zhang, Hongwen Guan, Na Zhong, Xuhui Zhang, Yanqin Ding, Jie Wang, Fang Front Genet Genetics Renal hypodysplasia and cystic kidney diseases, the common non-glomerular causes of pediatric chronic kidney disease (CKD), are usually diagnosed by their clinical and imaging characteristics. The high degree of phenotypic heterogeneity, in both conditions, makes the correct final diagnosis dependent on genetic testing. It is not clear, however, whether the frequencies of damaged alleles vary among different ethnicities in children with non-glomerular CKD, and this will influence the strategy used for genetic testing. In this study, 69 unrelated children (40 boys, 29 girls) of predominantly Han Chinese ethnicity with stage 2–5 non-glomerular CKD caused by suspected renal hypodysplasia or cystic kidney diseases were enrolled and assessed by molecular analysis using proband-only targeted exome sequencing and array-comparative genomic hybridization. Targeted exome sequencing discovered genetic etiologies in 33 patients (47.8%) covering 10 distinct genetic disorders. The clinical diagnoses in 13/48 patients (27.1%) with suspected renal hypodysplasia were confirmed, and two patients were reclassified carrying mutations in nephronophthisis (NPHP) genes. The clinical diagnoses in 16/20 patients (80%) with suspected cystic kidney diseases were confirmed, and one patient was reclassified as carrying a deletion in the hepatocyte nuclear factor-1-beta gene (HNF1B). The diagnosis of one patient with unknown non-glomerular disease was elucidated. No copy number variations were identified in the 20 patients with negative targeted exome sequencing results. NPHP genes were the most common disease-causing genes in the patients with disease onsets above 6 years of age (14/45, 31.1%). The children with stage 2 and 3 CKD at onset were found to carry causative mutations in paired box gene 2 (PAX2) and HNF1B gene (11/24, 45.8%), whereas those with stage 4 and 5 CKD mostly carried causative mutations in NPHP genes (19/45, 42.2%). The causative genes were not suspected by the kidney imaging patterns at disease onset. Thus, our data show that in Chinese children with non-glomerular renal dysfunction caused by renal hypodysplasia and cystic kidney diseases, the common causative genes vary with age and CKD stage at disease onset. These findings have the potential to improve management and genetic counseling of these diseases in clinical practice. Frontiers Media S.A. 2021-07-06 /pmc/articles/PMC8290170/ /pubmed/34295353 http://dx.doi.org/10.3389/fgene.2021.697085 Text en Copyright © 2021 Wang, Xiao, Yao, Xu, Liu, Su, Zhang, Guan, Zhong, Zhang, Ding and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Genetics
Wang, Xiaoyuan
Xiao, Huijie
Yao, Yong
Xu, Ke
Liu, Xiaoyu
Su, Baige
Zhang, Hongwen
Guan, Na
Zhong, Xuhui
Zhang, Yanqin
Ding, Jie
Wang, Fang
Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5
title Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5
title_full Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5
title_fullStr Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5
title_full_unstemmed Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5
title_short Spectrum of Mutations in Pediatric Non-glomerular Chronic Kidney Disease Stages 2–5
title_sort spectrum of mutations in pediatric non-glomerular chronic kidney disease stages 2–5
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290170/
https://www.ncbi.nlm.nih.gov/pubmed/34295353
http://dx.doi.org/10.3389/fgene.2021.697085
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