{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,8]],"date-time":"2026-07-08T02:11:18Z","timestamp":1783476678460,"version":"3.55.0"},"reference-count":73,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"CY-Biobank","award":["857122"],"award-info":[{"award-number":["857122"]}]},{"name":"CY-Biobank","award":["2016\u20132020\/INTEGRATED\/0918\/0043"],"award-info":[{"award-number":["2016\u20132020\/INTEGRATED\/0918\/0043"]}]},{"name":"European Renal Association-European Dialysis and Transplant Association (ERA-EDTA)","award":["857122"],"award-info":[{"award-number":["857122"]}]},{"name":"European Renal Association-European Dialysis and Transplant Association (ERA-EDTA)","award":["2016\u20132020\/INTEGRATED\/0918\/0043"],"award-info":[{"award-number":["2016\u20132020\/INTEGRATED\/0918\/0043"]}]},{"name":"European Reference Network for the European Rare Kidney Disease Reference Network, ERNnet","award":["857122"],"award-info":[{"award-number":["857122"]}]},{"name":"European Reference Network for the European Rare Kidney Disease Reference Network, ERNnet","award":["2016\u20132020\/INTEGRATED\/0918\/0043"],"award-info":[{"award-number":["2016\u20132020\/INTEGRATED\/0918\/0043"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Familial hematuria is a clinical sign of a genetically heterogeneous group of conditions, accompanied by broad inter- and intrafamilial variable expressivity. The most frequent condition is caused by pathogenic (or likely pathogenic) variants in the collagen-IV genes, COL4A3\/A4\/A5. Pathogenic variants in COL4A5 are responsible for the severe X-linked glomerulopathy, Alport syndrome (AS), while homozygous or compound heterozygous variants in the COL4A3 or the COL4A4 gene cause autosomal recessive AS. AS usually leads to progressive kidney failure before the age of 40-years when left untreated. People who inherit heterozygous COL4A3\/A4 variants are at-risk of a slowly progressive form of the disease, starting with microscopic hematuria in early childhood, developing Alport spectrum nephropathy. Sometimes, they are diagnosed with benign familial hematuria, and sometimes with autosomal dominant AS. At diagnosis, they often show thin basement membrane nephropathy, reflecting the uniform thin glomerular basement membrane lesion, inherited as an autosomal dominant condition. On a long follow-up, most patients will retain normal or mildly affected kidney function, while a substantial proportion will develop chronic kidney disease (CKD), even kidney failure at an average age of 55-years. A question that remains unanswered is how to distinguish those patients with AS or with heterozygous COL4A3\/A4 variants who will manifest a more aggressive kidney function decline, requiring prompt medical intervention. The hypothesis that a subgroup of patients coinherit additional genetic modifiers that exacerbate their clinical course has been investigated by several researchers. Here, we review all publications that describe the potential role of candidate genetic modifiers in patients and include a summary of studies in AS mouse models.<\/jats:p>","DOI":"10.3390\/genes14091686","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T08:25:33Z","timestamp":1692951933000},"page":"1686","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Genetic Modifiers of Mendelian Monogenic Collagen IV Nephropathies in Humans and Mice"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5549-9169","authenticated-orcid":false,"given":"Constantinos","family":"Deltas","sequence":"first","affiliation":[{"name":"School of Medicine, University of Cyprus, Nicosia 2109, Cyprus"},{"name":"biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Papagregoriou","sequence":"additional","affiliation":[{"name":"biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3000-3504","authenticated-orcid":false,"given":"Stavroula F.","family":"Louka","sequence":"additional","affiliation":[{"name":"biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1380-5521","authenticated-orcid":false,"given":"Apostolos","family":"Malatras","sequence":"additional","affiliation":[{"name":"biobank.cy Center of Excellence in Biobanking and Biomedical Research, University of Cyprus, Nicosia 2109, Cyprus"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances","family":"Flinter","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, Guy\u2019s & St Thomas\u2019 NHS Foundation Trust, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel P.","family":"Gale","sequence":"additional","affiliation":[{"name":"Department of Renal Medicine, University College London, London NW3 2PF, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susie","family":"Gear","sequence":"additional","affiliation":[{"name":"Alport UK, Tetbury GL8 0AW, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8390-8852","authenticated-orcid":false,"given":"Oliver","family":"Gross","sequence":"additional","affiliation":[{"name":"Clinic for Nephrology and Rheumatology, University Medicine Goettingen, 37075 Goettingen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Hoefele","sequence":"additional","affiliation":[{"name":"Institute of Human Genetics, Klinikum Rechts der Isar, School of Medicine & Health, Technical University Munich, 81675 Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Lennon","sequence":"additional","affiliation":[{"name":"Wellcome Centre for Cell-Matrix Research, University of Manchester, Manchester M13 9WU, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey H.","family":"Miner","sequence":"additional","affiliation":[{"name":"Division of Nephrology, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0846-9220","authenticated-orcid":false,"given":"Alessandra","family":"Renieri","sequence":"additional","affiliation":[{"name":"Medical Genetics, University of Siena, 53100 Siena, Italy"},{"name":"Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy"},{"name":"Genetica Medica, Azienda Ospedaliero-Universitaria Senese, 53100 Siena, Italy"}],"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, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4547-873X","authenticated-orcid":false,"given":"A. Neil","family":"Turner","sequence":"additional","affiliation":[{"name":"Renal Medicine, Royal Infirmary, University of Edinburgh, Edinburgh EH16 4UX, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"100631","DOI":"10.1016\/j.xkme.2023.100631","article-title":"Alport Syndrome: Clinical Spectrum and Therapeutic Advances","volume":"5","author":"Caparali","year":"2023","journal-title":"Kidney Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/S0140-6736(88)90753-2","article-title":"Genetics of classic Alport\u2019s syndrome","volume":"2","author":"Flinter","year":"1988","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"4013","DOI":"10.1113\/jphysiol.2014.274449","article-title":"Alport syndrome: Its effects on the glomerular filtration barrier and implications for future treatment","volume":"592","author":"Savige","year":"2014","journal-title":"J. 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