{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T05:55:24Z","timestamp":1785477324961,"version":"3.56.0"},"reference-count":24,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2705103"],"award-info":[{"award-number":["2022YFC2705103"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2022YFC2705100"],"award-info":[{"award-number":["2022YFC2705100"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["LTGD24H050002"],"award-info":[{"award-number":["LTGD24H050002"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["2022YFC2705103"],"award-info":[{"award-number":["2022YFC2705103"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["2022YFC2705100"],"award-info":[{"award-number":["2022YFC2705100"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004731","name":"Natural Science Foundation of Zhejiang Province","doi-asserted-by":"publisher","award":["LTGD24H050002"],"award-info":[{"award-number":["LTGD24H050002"]}],"id":[{"id":"10.13039\/501100004731","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medicina"],"abstract":"<jats:p>Background and Objectives: PAX2 serves as a critical transcription factor integral to the process of embryogenesis. Variations in the PAX2 gene could result in the aberrant development of numerous organs. Despite the identification of numerous mutations within the PAX2 gene, the correlation between specific genotypes has yet to be fully clarified. The objective of this study was to examine the clinical phenotypes and genotypes associated with PAX2 mutation-induced disorders in pediatric patients of Chinese descent. The aim of our study was to forecast the pathogenic potential of these genetic mutations and to ascertain possible correlations between genotypic variations and the clinical manifestations of disorders linked to PAX2 mutations. Materials and Methods: We recruited 14 pediatric subjects with PAX2 mutations, meticulously examining the clinical characteristics and genetic alterations present in these individuals. Computational techniques were utilized to evaluate the pathogenicity, stability, and biophysical characteristics. A range of computational tools were employed for this assessment, including PredictSNP, MAGPIE, iStable, Align GVGD, ConSurf, and SNP effect. Results: The age at onset ranged from prenatal to 12 years. Five patients progressed to end-stage renal disease. Proteinuria and bilateral renal hypoplasia were observed in 92% of cases. Ocular and auditory abnormalities were also noted. We identified eleven different PAX2 mutations, including five novel variants not previously reported in the literature. We predicted that all mutations, with the exception of p.F27-L33 del and N188S, exhibited high pathogenicity scores. In particular, R117P and R140W are strongly associated with disease pathogenicity and are likely to cause more significant damage than other gene mutants. Conclusions: This study expands the mutational and phenotypic spectrum of PAX2-related disorders in the pediatric population. The identification of five novel variants enhances our understanding of the genetic basis of these conditions. Despite recurrent mutations, marked phenotypic heterogeneity persists, underscoring the need for further research.<\/jats:p>","DOI":"10.3390\/medicina61060959","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T12:15:43Z","timestamp":1747916143000},"page":"959","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical Characteristics and Genetic Variants in Children with PAX2 Mutation-Associated Disorders"],"prefix":"10.3390","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5822-8962","authenticated-orcid":false,"given":"Yanyan","family":"Jin","sequence":"first","affiliation":[{"name":"Department of Nephrology, The Children\u2019s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Na","family":"Li","sequence":"additional","affiliation":[{"name":"School of Medicine, Zhejiang University, Hangzhou 310027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zipei","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, Zhejiang University, Hangzhou 310027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ke","family":"Zeng","sequence":"additional","affiliation":[{"name":"Department of Pediatric, The First Affiliated Hospital of Ningbo University, Ningbo 315211, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Children\u2019s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiqin","family":"Sheng","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Children\u2019s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haidong","family":"Fu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Children\u2019s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1145-2745","authenticated-orcid":false,"given":"Lidan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Children\u2019s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6076-3806","authenticated-orcid":false,"given":"Jianhua","family":"Mao","sequence":"additional","affiliation":[{"name":"Department of Nephrology, The Children\u2019s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"ref_1","first-page":"701","article-title":"Expression of PAX2 gene during human development","volume":"42","author":"Muller","year":"1998","journal-title":"Int. J. Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4057","DOI":"10.1242\/dev.121.12.4057","article-title":"Pax-2 controls multiple steps of urogenital development","volume":"121","author":"Torres","year":"1995","journal-title":"Development"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1007\/s00439-020-02212-9","article-title":"Overview of PAX gene family: Analysis of human tissue-specific variant expression and involvement in human disease","volume":"140","author":"Thompson","year":"2021","journal-title":"Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1007\/s00467-011-2053-0","article-title":"PAX2 in human kidney malformations and disease","volume":"27","author":"Harshman","year":"2012","journal-title":"Pediatr. Nephrol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Muntean, C., Chirtes, C., Baczoni, B., and Banescu, C. (2023). PAX2 Gene Mutation in Pediatric Renal Disorders-A Narrative Review. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241612737"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1002\/humu.22020","article-title":"Update of PAX2 mutations in renal coloboma syndrome and establishment of a locus-specific database","volume":"33","author":"Bower","year":"2012","journal-title":"Hum. Mutat."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1097\/MOP.0b013e32834fdbd4","article-title":"Novel genetic aspects of congenital anomalies of kidney and urinary tract","volume":"24","author":"Weber","year":"2012","journal-title":"Curr. Opin. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e93","DOI":"10.1002\/cphg.93","article-title":"Overview of Specifications to the ACMG\/AMP Variant Interpretation Guidelines","volume":"103","author":"Harrison","year":"2019","journal-title":"Curr. Protoc. Hum. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Bendl, J., Stourac, J., Salanda, O., Pavelka, A., Wieben, E.D., Zendulka, J., Brezovsky, J., and Damborsky, J. (2014). PredictSNP: Robust and accurate consensus classifier for prediction of disease-related mutations. PLoS Comput. Biol., 10.","DOI":"10.1371\/journal.pcbi.1003440"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"S2","DOI":"10.1186\/1471-2105-14-S2-S5","article-title":"iStable: Off-the-shelf predictor integration for predicting protein stability changes","volume":"14","author":"Chen","year":"2013","journal-title":"BMC Bioinform."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1136\/jmg.2005.033878","article-title":"Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral","volume":"43","author":"Tavtigian","year":"2006","journal-title":"J. Med. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1093\/bioinformatics\/19.1.163","article-title":"ConSurf: Identification of functional regions in proteins by surface-mapping of phylogenetic information","volume":"19","author":"Glaser","year":"2003","journal-title":"Bioinformatics"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s13073-023-01274-4","article-title":"MAGPIE: Accurate pathogenic prediction for multiple variant types using machine learning approach","volume":"16","author":"Liu","year":"2024","journal-title":"Genome Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1007\/s00467-021-05303-5","article-title":"Kidney length normative values in children aged 0\u201319 years\u2014A multicenter study","volume":"37","author":"Obrycki","year":"2022","journal-title":"Pediatr. Nephrol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yang, X., Li, Y., Fang, Y., Shi, H., Xiang, T., Liu, J., Liu, J., Tang, X., Fang, X., and Chen, J. (2021). Phenotypic spectrum and genetics of PAX2-related disorder in the Chinese cohort. BMC Med. Genom., 14.","DOI":"10.1186\/s12920-021-01102-x"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Zhang, L., Zhai, S.-B., Zhao, L.-Y., Zhang, Y., Sun, B.-C., and Ma, Q.-S. (2018). New PAX2 heterozygous mutation in a child with chronic kidney disease: A case report and review of the literature. BMC Nephrol., 19.","DOI":"10.1186\/s12882-018-1044-9"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e701","DOI":"10.1002\/mgg3.701","article-title":"Diverse phenotypes in children with PAX2-related disorder","volume":"7","author":"Deng","year":"2019","journal-title":"Mol. Genet. Genom. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1007\/s00467-012-2205-x","article-title":"Discordant phenotype in monozygotic twins with renal coloboma syndrome and a PAX2 mutation","volume":"27","author":"Iatropoulos","year":"2012","journal-title":"Pediatr. Nephrol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1093\/hmg\/9.1.1","article-title":"Primary renal hypoplasia in humans and mice with PAX2 mutations: Evidence of increased apoptosis in fetal kidneys of Pax2(1Neu) +\/\u2212 mutant mice","volume":"9","author":"Porteous","year":"2000","journal-title":"Hum. Mol. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1055","DOI":"10.1007\/s00467-015-3228-x","article-title":"Epigenetics mechanisms in renal development","volume":"31","author":"Hilliard","year":"2016","journal-title":"Pediatr. Nephrol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1681\/ASN.2006101107","article-title":"A common variant of the PAX2 gene is associated with reduced newborn kidney size","volume":"18","author":"Quinlan","year":"2007","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1186\/s40001-025-02522-6","article-title":"Clinical spectrum, genetics and management insights of PAX2-related disorder in nine children","volume":"30","author":"Min","year":"2025","journal-title":"Eur. J. Med. Res."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Negrisolo, S., and Benetti, E. (2023). PAX2 and CAKUT Phenotypes: Report on Two New Variants and a Review of Mutations from the Leiden Open Variation Database. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24044165"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Xiong, H.Y., Shi, Y.Q., Zhong, C., Yang, Q., Zhang, G., Yang, H., Wu, D., Chen, Y., Li, Q., and Wang, M. (2022). Detection of De Novo PAX2 Variants and Phenotypes in Chinese Population: A Single-Center Study. Front. Genet., 13.","DOI":"10.3389\/fgene.2022.799562"}],"container-title":["Medicina"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1648-9144\/61\/6\/959\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:38:42Z","timestamp":1760031522000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1648-9144\/61\/6\/959"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,22]]},"references-count":24,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["medicina61060959"],"URL":"https:\/\/doi.org\/10.3390\/medicina61060959","relation":{},"ISSN":["1648-9144"],"issn-type":[{"value":"1648-9144","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,22]]}}}