{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T10:07:12Z","timestamp":1790158032983,"version":"4.1.0"},"reference-count":22,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:00:00Z","timestamp":1790121600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Nephrology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"ABSTRACT<\/jats:title>\n \n Aim<\/jats:title>\n Primary hyperoxaluria (PH) represents a rare genetic disorder characterised by incompletely elucidated causative genes and limited therapeutic options. This study aims to identify PH\u2010associated genetic variants and potential drug targets.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n We performed exon sequencing of eight PH patients to find PH\u2010related mutant genes, and used the PH rat model to explore differentially expressed genes related to PH. Key core genes related to PH are identified through functional enrichment analysis and protein interaction analysis.<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n Whole\u2010exome sequencing of eight patients with a clinical diagnosis of Primary Hyperoxaluria Type 1 (PH1) identified biallelic pathogenic or likely pathogenic\n AGXT<\/jats:italic>\n variants in five individuals. One patient was partially confirmed, and two patients were clinically confirmed only. Additional rare variants were detected across\n AGXT<\/jats:italic>\n ,\n GRHPR<\/jats:italic>\n ,\n HOGA1<\/jats:italic>\n ,\n PEX1<\/jats:italic>\n and\n OxGR1<\/jats:italic>\n ; variants in intronic regions were retained only if predicted to affect splicing. In total, two patients harboured \u2265\u200920 rare variants in\n AGXT<\/jats:italic>\n , and four patients had >\u200910 rare variants in\n PEX1<\/jats:italic>\n . Across five candidate genes, 548 shared variant\u2010bearing genes were enriched in cytoskeletal organization and cell adhesion. SNV analysis showed frameshift insertions and deletions as the most frequent mutation types, and\n AGAP3<\/jats:italic>\n and SON were the most heavily mutated, implicating NK cell regulation. Germline rare variant load\u2014defined as the total number of rare variants (MAF\u2009<\u20091%) per patient identified by WES\u2014showed a negative correlation with serum creatinine, blood urea nitrogen, phosphorus and PTH levels, and was elevated in patients from consanguineous families, suggesting that a higher degree of genomic homozygosity may modify disease phenotype. A total of 678 differentially expressed genes were found in differential expression analysis of the PH model. These genes were mainly related to mitochondrial function. Through cross\u2010analysis, a total of 347 genes were found. These genes exhibited both differential expression in the rat model and rare germline variants in patient WES data. Through module screening, two key modules were found, which were mainly related to cell\u2010cycle\/mitotic processes and immune response. Comparative analysis of patients with and without nephrolithiasis identified 22 genes with nominally differential distribution; this finding is exploratory and requires validation in larger cohorts.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n This study provides new insights into PH pathogenesis through integrative WES and transcriptomic analysis, identifying hypothesis\u2010generating candidate genes potentially linked to nephrolithiasis susceptibility in this small cohort that warrant further functional validation in larger, independent populations.<\/jats:p>\n <\/jats:sec>","DOI":"10.1111\/nep.70279","type":"journal-article","created":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T09:26:49Z","timestamp":1790155609000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrative Genomic and Transcriptomic Analysis Reveals Hypothesis\u2010Generating Candidate Genes for Nephrolithiasis Susceptibility in Primary Hyperoxaluria"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-0464-6293","authenticated-orcid":false,"given":"Yan","family":"Li","sequence":"first","affiliation":[{"name":"Nephrology Department The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Kidney Transplantation The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueyan","family":"Lin","sequence":"additional","affiliation":[{"name":"Nephrology Department The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Lv","sequence":"additional","affiliation":[{"name":"Nephrology Department The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyu","family":"Yang","sequence":"additional","affiliation":[{"name":"Nephrology Department The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Han","sequence":"additional","affiliation":[{"name":"Nephrology Department The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanhong","family":"Lu","sequence":"additional","affiliation":[{"name":"Nephrology Department The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingzhong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Cardiovascular Medicine The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,23]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","doi-asserted-by":"crossref","DOI":"10.1002\/jimd.12817","article-title":"Human Glyoxylate Metabolism Revisited: New Insights Pointing to Multi\u2010Organ Involvement With Implications for siRNA\u2010Based Therapies in Primary Hyperoxaluria","volume":"48","author":"Wanders R. J. A.","year":"2025","journal-title":"Journal of Inherited Metabolic Disease"},{"issue":"4","key":"e_1_2_12_3_1","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1159\/000539516","article-title":"Mutation Characteristics of Primary Hyperoxaluria in the Chinese Population and Current International Diagnosis and Treatment Status","volume":"10","author":"Zhu X.","year":"2024","journal-title":"Kidney Disease"},{"issue":"6","key":"e_1_2_12_4_1","first-page":"856","article-title":"Infant Primary Hyperoxaluria Type 1: A Case Report and Literature Review","volume":"49","author":"Zheng Y.","year":"2024","journal-title":"Zhong Nan Da Xue Xue Bao. Yi Xue Ban"},{"issue":"2","key":"e_1_2_12_5_1","first-page":"169","article-title":"Research Progress on Renal Calculus Associate With Inborn Error of Metabolism","volume":"52","author":"Song Y.","year":"2023","journal-title":"Zhejiang Da Xue Xue Bao. Yi Xue Ban"},{"issue":"3","key":"e_1_2_12_6_1","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00467-022-05613-2","article-title":"Genetic Assessment in Primary Hyperoxaluria: Why It Matters","volume":"38","author":"Mandrile G.","year":"2023","journal-title":"Pediatric Nephrology"},{"issue":"1","key":"e_1_2_12_7_1","doi-asserted-by":"crossref","first-page":"i33","DOI":"10.1093\/ckj\/sfab203","article-title":"Primary Hyperoxaluria Type 1 in Developing Countries: Novel Challenges in a New Therapeutic Era","volume":"15","author":"Soliman N. A.","year":"2022","journal-title":"Clinical Kidney Journal"},{"issue":"1","key":"e_1_2_12_8_1","doi-asserted-by":"crossref","first-page":"i17","DOI":"10.1093\/ckj\/sfab245","article-title":"Primary Hyperoxaluria Type 1: Novel Therapies at a Glance","volume":"15","author":"Bacchetta J.","year":"2022","journal-title":"Clinical Kidney Journal"},{"issue":"12","key":"e_1_2_12_9_1","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1002\/humu.24490","article-title":"HOGA1 Gene Pathogenic Variants in Primary Hyperoxaluria Type III: Spectrum of Pathogenic Sequence Variants, and Phenotypic Association","volume":"43","author":"Abid A.","year":"2022","journal-title":"Human Mutation"},{"issue":"2","key":"e_1_2_12_10_1","first-page":"129","article-title":"Clinical Analysis of Seven Cases With Primary Hyperoxaluria Type 1 in Children","volume":"58","author":"Liao X.","year":"2020","journal-title":"Zhonghua Er Ke Za Zhi"},{"issue":"9","key":"e_1_2_12_11_1","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1369\/0022155419849388","article-title":"Extracellular Matrix in Kidney Fibrosis: More Than Just a Scaffold","volume":"67","author":"Bulow R. 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