{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T05:49:33Z","timestamp":1790660973710,"version":"4.1.0"},"reference-count":44,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"11","content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["CJASN"],"published-print":{"date-parts":[[2022,11]]},"abstract":"\n Digenic Alport syndrome refers to the inheritance of pathogenic variants in\n COL4A5<\/jats:italic>\n plus\n COL4A3<\/jats:italic>\n or\n COL4A4<\/jats:italic>\n or in\n COL4A3<\/jats:italic>\n plus\n COL4A4<\/jats:italic>\n . Where digenic Alport syndrome includes a pathogenic\n COL4A5<\/jats:italic>\n variant, the consequences depend on the sex of the affected individual,\n COL4A5<\/jats:italic>\n variant \u201cseverity,\u201d and the nature of the\n COL4A3<\/jats:italic>\n or\n COL4A4<\/jats:italic>\n change. A man with a pathogenic\n COL4A5<\/jats:italic>\n variant has all his collagen IV\n \u03b1<\/jats:italic>\n 3\n \u03b1<\/jats:italic>\n 4\n \u03b1<\/jats:italic>\n 5-heterotrimers affected, and an additional\n COL4A3<\/jats:italic>\n or\n COL4A4<\/jats:italic>\n variant may not worsen disease. A woman with a pathogenic\n COL4A5<\/jats:italic>\n variant has on average 50% of her heterotrimers affected, which is increased to 75% with a further\n COL4A3<\/jats:italic>\n or\n COL4A4<\/jats:italic>\n variant and associated with a higher risk of proteinuria. In digenic Alport syndrome with pathogenic\n COL4A3<\/jats:italic>\n and\n COL4A4<\/jats:italic>\n variants, 75% of the heterotrimers are affected. The\n COL4A3<\/jats:italic>\n and\n COL4A4<\/jats:italic>\n genes occur head-to-head on chromosome 2, and inheritance is autosomal dominant when both variants affect the same chromosome (\n in cis<\/jats:italic>\n ) or recessive when they affect different chromosomes (\n in trans<\/jats:italic>\n ). This form of digenic disease results in increased proteinuria and a median age of kidney failure intermediate between autosomal dominant and autosomal recessive Alport syndrome. Previous guidelines have suggested that all pathogenic or likely pathogenic digenic variants should be identified and reported. Affected family members should be identified, treated, and discouraged from kidney donation. Inheritance within a family is easier to predict if the two variants are considered independently and if\n COL4A3<\/jats:italic>\n and\n COL4A4<\/jats:italic>\n variants are known to be inherited on the same or different chromosomes.\n <\/jats:p>","DOI":"10.2215\/cjn.03120322","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T10:10:25Z","timestamp":1654683025000},"page":"1697-1706","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":56,"title":["Digenic Alport Syndrome"],"prefix":"10.2215","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6813-0288","authenticated-orcid":false,"given":"Judy","family":"Savige","sequence":"first","affiliation":[{"name":"Department of Medicine (Melbourne Health and Northern Health), The University of Melbourne, Parkville, Victoria, 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University College London, London, United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3699-1884","authenticated-orcid":false,"given":"Marina","family":"Aksenova","sequence":"additional","affiliation":[{"name":"Department of Nephrology, Veltischev Research and Clinical Institute for Pediatrics of the Pirogov Russian National Research Medical University, Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Agne","family":"Cerkauskaite","sequence":"additional","affiliation":[{"name":"Division of Diagnostics and Treatment of Rare Kidney and Metabolic Diseases, Institute of Biomedical Sciences, Vilnius University, Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Bielska","sequence":"additional","affiliation":[{"name":"Centre for Rare Diseases and Clinical Genetics Unit, Medical University of Gdansk, Gdansk, 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