{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T23:26:43Z","timestamp":1783121203513,"version":"3.54.6"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T00:00:00Z","timestamp":1772409600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>One in seven people with IgA nephropathy has another apparently-affected family member. This study examined how often biopsy-proven familial and sporadic IgA nephropathy were associated with genetic kidney disease.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Eleven unrelated people with biopsy-proven IgA nephropathy and another family member with kidney tests compatible with IgA nephropathy were recruited. All available family members were assessed for genetic kidney disease, using Whole Exome Sequencing (WES). Their results were compared with those of 39 people with sporadic IgA nephropathy. All sequencing results were filtered for pathogenic variants in genes associated with genetic kidney disease (Genomics England panels,\n                      <jats:italic>n<\/jats:italic>\n                      \u202f=\u202f384). Variants were assessed for pathogenicity using ClinVar and the ACMG\/AMP criteria in Alamut.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nine of the 11 probands (82%) with familial nephropathy and 30 of those with sporadic disease (77%) had kidney failure. At least five (45%) and possibly nine (82%) of the 11 families studied had disease-associated heterozygous variants consistent with a coexistent genetic kidney disease (autosomal dominant (AD) and X-linked (XL) Alport syndrome, ADTKD-\n                      <jats:italic>HNF1B<\/jats:italic>\n                      , and possibly Dent disease, Focal and Segmental Glomerulosclerosis (FSGS), and CHARGE syndrome). Inheritance for all these diseases was AD or X-linked. Sometimes the proband with IgA nephropathy did not have the genetic variant found in other apparently-affected family members. Sometimes two genetic variants corresponding to two different diseases were present in the same family. Two of the 39 people with sporadic IgA nephropathy (5%) also had disease-causing variants consistent with genetic kidney disease (AD Alport syndrome, cystinuria).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Many familial cases of IgA nephropathy result from mesangial IgA deposition in the setting of coexisting genetic kidney disease. Sometimes, genetic kidney disease is not detected in the proband but is present in another family member. Individuals from families with IgA nephropathy should be offered genetic testing.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2025.1647695","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T05:21:11Z","timestamp":1772428871000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Coexisting genetic kidney disease explains many cases of \u2018familial\u2019 IgA nephropathy where the proband has biopsy-confirmed mesangial IgA deposits"],"prefix":"10.3389","volume":"12","author":[{"given":"YuXin","family":"Li","sequence":"first","affiliation":[{"name":"Department of Medicine, Melbourne Health and Northern Health, The University of Melbourne","place":["Parkville, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Melbourne Health and Northern Health, The University of Melbourne","place":["Parkville, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo Jun","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Melbourne Health and Northern Health, The University of Melbourne","place":["Parkville, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ziming","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Medicine, Melbourne Health and Northern Health, The University of Melbourne","place":["Parkville, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bocheng","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Melbourne Health and Northern Health, The University of Melbourne","place":["Parkville, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Khalid","family":"Mahmood","sequence":"additional","affiliation":[{"name":"Melbourne Bioinformatics, The University of Melbourne","place":["Parkville, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deb","family":"Colville","sequence":"additional","affiliation":[{"name":"Department of Surgery (Ophthalmology), Royal Victorian Eye and Ear Hospital","place":["East Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Barit","sequence":"additional","affiliation":[{"name":"Renal Unit, Northern Health","place":["Epping, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Russell","family":"Auwardt","sequence":"additional","affiliation":[{"name":"Renal Unit, Albury Hospital","place":["Albury-Wodonga, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Fassett","sequence":"additional","affiliation":[{"name":"Tasmanian Health Service, North West","place":["Burnie, TAS, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathy","family":"Paizis","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Austin Health","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Ierino","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Austin Health","place":["Melbourne, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy","family":"Pianta","sequence":"additional","affiliation":[{"name":"Renal Unit, Northern Health","place":["Epping, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Langsford","sequence":"additional","affiliation":[{"name":"Renal Unit, Northern Health","place":["Epping, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mary","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Melbourne Health and Northern Health, The University of Melbourne","place":["Parkville, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy","family":"Savige","sequence":"additional","affiliation":[{"name":"Department of Medicine, Melbourne Health and Northern Health, The University of Melbourne","place":["Parkville, VIC, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,2]]},"reference":[{"key":"ref1","first-page":"709","article-title":"The commonest glomerulonephritis in the world: IgA nephropathy","volume":"64","author":"D'Amico","year":"1987","journal-title":"Q J Med"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1016\/j.semnephrol.2018.05.013","article-title":"Epidemiology of IgA nephropathy: a global perspective","volume":"38","author":"Schena","year":"2018","journal-title":"Semin Nephrol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1053\/ajkd.2000.8966","article-title":"Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors","volume":"36","author":"D'Amico","year":"2000","journal-title":"Am J Kidney Dis"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1111\/nep.12629","article-title":"Long-term outcomes of end-stage kidney disease for patients with IgA nephropathy: a multi-centre registry study","volume":"21","author":"Zhang","year":"2016","journal-title":"Nephrology"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"1795","DOI":"10.1681\/ASN.2011050464","article-title":"The pathophysiology of IgA nephropathy","volume":"22","author":"Suzuki","year":"2011","journal-title":"J Am Soc Nephrol"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1007\/s00467-003-1387-7","article-title":"Henoch-Schonlein purpura nephritis associated with Epstein-Barr virus infection in twins","volume":"19","author":"Kim","year":"2004","journal-title":"Pediatr Nephrol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"1077","DOI":"10.1046\/j.1523-1755.2001.0590031077.x","article-title":"Mass spectrometry proves under-O-glycosylation of glomerular IgA1 in IgA nephropathy","volume":"59","author":"Hiki","year":"2001","journal-title":"Kidney Int"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1172\/JCI5535","article-title":"Circulating immune complexes in IgA nephropathy consist of IgA1 with galactose-deficient hinge region and antiglycan antibodies","volume":"104","author":"Tomana","year":"1999","journal-title":"J Clin Invest"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1159\/000045212","article-title":"Deposition of mannan binding protein and mannan binding protein-mediated complement activation in the glomeruli of patients with IgA nephropathy","volume":"80","author":"Matsuda","year":"1998","journal-title":"Nephron"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1016\/s0272-6386(99)70417-8","article-title":"Familial clustering of IgA nephropathy: further evidence in an Italian population","volume":"33","author":"Scolari","year":"1999","journal-title":"Am J Kidney Dis"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"230","DOI":"10.1186\/s12882-021-02425-8","article-title":"Positive renal familial history in IgA nephropathy is associated with worse renal outcomes: a single-center longitudinal study","volume":"22","author":"Sato","year":"2021","journal-title":"BMC Nephrol"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1016\/j.ekir.2020.10.015","article-title":"Increased lifetime risk of ESRD in familial IgA nephropathy","volume":"6","author":"Shi","year":"2021","journal-title":"Kidney Int Rep"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/sj.ki.5002088","article-title":"Variants of C1GALT1 gene are associated with the genetic susceptibility to IgA nephropathy","volume":"71","author":"Li","year":"2007","journal-title":"Kidney Int"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"e1002765","DOI":"10.1371\/journal.pgen.1002765","article-title":"Geographic differences in genetic susceptibility to IgA nephropathy: GWAS replication study and geospatial risk analysis","volume":"8","author":"Kiryluk","year":"2012","journal-title":"PLoS Genet"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"943","DOI":"10.1093\/ndt\/4.11.943","article-title":"Frequency of mesangial IgA deposits in a non-selected autopsy series","volume":"4","author":"Waldherr","year":"1989","journal-title":"Nephrol Dial Transplant"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"2286","DOI":"10.1046\/j.1523-1755.63.6s.2.x","article-title":"Incidence of latent mesangial IgA deposition in renal allograft donors in Japan","volume":"63","author":"Suzuki","year":"2003","journal-title":"Kidney Int"},{"key":"ref17","doi-asserted-by":"publisher","first-page":"607","DOI":"10.1136\/jcp.46.7.607","article-title":"Immunoglobulin and complement deposition in glomeruli of 756 subjects who had committed suicide or met with a violent death","volume":"46","author":"Varis","year":"1993","journal-title":"J Clin Pathol"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"1791","DOI":"10.1681\/ASN.2010010076","article-title":"HLA has strongest association with IgA nephropathy in genome-wide analysis","volume":"21","author":"Feehally","year":"2010","journal-title":"J Am Soc Nephrol"},{"key":"ref19","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/ng.787","article-title":"Genome-wide association study identifies susceptibility loci for IgA nephropathy","volume":"43","author":"Gharavi","year":"2011","journal-title":"Nat Genet"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1038\/ng.1047","article-title":"A genome-wide association study in Han Chinese identifies multiple susceptibility loci for IgA nephropathy","volume":"44","author":"Yu","year":"2011","journal-title":"Nat Genet"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1038\/ng.3118","article-title":"Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens","volume":"46","author":"Kiryluk","year":"2014","journal-title":"Nat Genet"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1016\/j.autrev.2017.11.024","article-title":"Genetics of immunoglobulin-A vasculitis (Henoch-Sch\u00f6nlein purpura): an updated review","volume":"17","author":"Lopez-Mejias","year":"2018","journal-title":"Autoimmun Rev"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"510","DOI":"10.1038\/ng.3528","article-title":"Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci","volume":"48","author":"Ellinghaus","year":"2016","journal-title":"Nat Genet"},{"key":"ref24","first-page":"730","article-title":"Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci","volume-title":"Nat Genet","author":"Cortes","year":"2013"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"1673","DOI":"10.1038\/ejhg.2015.52","article-title":"A SPRY2 mutation leading to MAPK\/ERK pathway inhibition is associated with an autosomal dominant form of IgA nephropathy","volume":"23","author":"Milillo","year":"2015","journal-title":"Eur J Hum Genet"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1038\/ki.1992.412","article-title":"IgA nephropathy in patients with congenital C9 deficiency","volume":"42","author":"Yoshioka","year":"1992","journal-title":"Kidney Int"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"1503","DOI":"10.1681\/ASN.2014101000","article-title":"Current understanding of the role of complement in IgA nephropathy","volume":"26","author":"Maillard","year":"2015","journal-title":"J Am Soc Nephrol"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"1075","DOI":"10.1016\/j.ekir.2020.04.011","article-title":"Type IV collagen mutations in familial IgA nephropathy","volume":"5","author":"Li","year":"2020","journal-title":"Kidney Int Rep"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1159\/000503564","article-title":"An exome sequencing study of 10 families with IgA nephropathy","volume":"144","author":"Stapleton","year":"2020","journal-title":"Nephron"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"674","DOI":"10.3760\/cma.j.issn.0578-1310.2019.09.006","article-title":"Genetic variants of familial hematuria associated genes in three families with hematuria with probands initially diagnosed as IgA nephropathy","volume":"57","author":"Liu","year":"2019","journal-title":"Zhonghua Er Ke Za Zhi"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"2408","DOI":"10.1681\/ASN.2007020241","article-title":"Genome-wide linkage scan of a large family with IgA nephropathy localizes a novel susceptibility locus to chromosome 2q36","volume":"18","author":"Paterson","year":"2007","journal-title":"J Am Soc Nephrol"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"2273","DOI":"10.1681\/ASN.2020071065","article-title":"Prevalence estimates of predicted pathogenic COL4A3-COL4A5 variants in a population sequencing database and their implications for Alport syndrome","volume":"32","author":"Gibson","year":"2021","journal-title":"J Am Soc Nephrol"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"393","DOI":"10.1038\/ng1297-393","article-title":"Positional cloning of the APECED gene","volume":"17","author":"Nagamine","year":"1997","journal-title":"Nat Genet"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1038\/ng1297-399","article-title":"An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains","volume":"17","year":"1997","journal-title":"Nat Genet"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/ng.806","article-title":"A framework for variation discovery and genotyping using next-generation DNA sequencing data","volume":"43","author":"DePristo","year":"2011","journal-title":"Nat Genet"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The Ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/s41586-020-2308-7","article-title":"The mutational constraint spectrum quantified from variation in 141,456 humans","volume":"581","author":"Karczewski","year":"2020","journal-title":"Nature"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"248","DOI":"10.1038\/nmeth0410-248","article-title":"A method and server for predicting damaging missense mutations","volume":"7","author":"Adzhubei","year":"2010","journal-title":"Nat Methods"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"3812","DOI":"10.1093\/nar\/gkg509","article-title":"SIFT: predicting amino acid changes that affect protein function","volume":"31","author":"Ng","year":"2003","journal-title":"Nucleic Acids Res"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat Methods"},{"key":"ref42","doi-asserted-by":"crossref","DOI":"10.21203\/rs.3.rs-2844330\/v1","article-title":"Autosomal dominant tubulointerstitial kidney disease cosegregating with COL4A4:p.G545A in Turkish Cypriot families with kidney failure","author":"Ozdemir","year":""},{"key":"ref43","doi-asserted-by":"publisher","first-page":"2201","DOI":"10.1007\/s00467-008-0934-7","article-title":"The R229Q mutation in NPHS2 may predispose to proteinuria in thin-basement-membrane nephropathy","volume":"23","author":"Tonna","year":"2008","journal-title":"Pediatr Nephrol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"1659","DOI":"10.1172\/JCI16242","article-title":"NPHS2 mutations in late-onset focal segmental glomerulosclerosis: R229Q is a common disease-associated allele","volume":"110","author":"Tsukaguchi","year":"2002","journal-title":"J Clin Invest"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"52","DOI":"10.2169\/internalmedicine.40.52","article-title":"IgA nephropathy with complement deficiency","volume":"40","author":"Kanda","year":"2001","journal-title":"Intern Med"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.ejmg.2018.04.003","article-title":"Genetic analysis of Charcot-Marie-tooth disease in Denmark and the implementation of a next generation sequencing platform","volume":"62","author":"Vaeth","year":"2019","journal-title":"Eur J Med Genet"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"363","DOI":"10.1016\/j.kint.2018.02.027","article-title":"A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases","volume":"94","author":"Bullich","year":"2018","journal-title":"Kidney Int"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1093\/ndt\/gfab019","article-title":"Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players","volume":"37","author":"Domingo-Gallego","year":"2022","journal-title":"Nephrol Dial Transplant"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s41525-023-00362-z","article-title":"Atypical splicing variants in PKD1 explain most undiagnosed typical familial ADPKD","volume":"8","author":"Hort","year":"2023","journal-title":"NPJ Genom Med"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"1933","DOI":"10.1016\/j.ekir.2022.06.001","article-title":"Heterozygous pathogenic COL4A3 and COL4A4 variants (autosomal dominant Alport syndrome) are common, and not typically associated with end-stage kidney failure, hearing loss, or ocular abnormalities","volume":"7","author":"Savige","year":"2022","journal-title":"Kidney Int Rep"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.2215\/CJN.00580116","article-title":"Alport syndrome in women and girls","volume":"11","author":"Savige","year":"2016","journal-title":"Clin J Am Soc Nephrol"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"142","DOI":"10.1056\/NEJMoa1806891","article-title":"Diagnostic utility of exome sequencing for kidney disease","volume":"380","author":"Groopman","year":"2019","journal-title":"N Engl J Med"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1647695\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T05:21:13Z","timestamp":1772428873000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1647695\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,2]]},"references-count":52,"alternative-id":["10.3389\/fmed.2025.1647695"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1647695","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,2]]},"article-number":"1647695"}}