{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:21:59Z","timestamp":1790878919420,"version":"4.1.0"},"reference-count":36,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T00:00:00Z","timestamp":1705017600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HO 2583\/13\u20101"],"award-info":[{"award-number":["HO 2583\/13\u20101"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Genetics"],"published-print":{"date-parts":[[2024,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Alport syndrome (AS) shows a broad phenotypic spectrum ranging from isolated microscopic hematuria (MH) to end\u2010stage kidney disease (ESKD). Monoallelic disease\u2010causing variants in <jats:italic>COL4A3<\/jats:italic>\/<jats:italic>COL4A4<\/jats:italic> have been associated with autosomal dominant AS (ADAS) and biallelic variants with autosomal recessive AS (ARAS). The aim of this study was to analyze clinical and genetic data regarding a possible genotype\u2013phenotype correlation in individuals with disease\u2010causing variants in <jats:italic>COL4A3<\/jats:italic>\/<jats:italic>COL4A4<\/jats:italic>. Eighty\u2010nine individuals carrying at least one <jats:italic>COL4A3<\/jats:italic>\/<jats:italic>COL4A4<\/jats:italic> variant classified as (likely) pathogenic according to the American College of Medical Genetics guidelines and current amendments were recruited. Clinical data concerning the prevalence and age of first reported manifestation of MH, proteinuria, ESKD, and extrarenal manifestations were collected. Individuals with monoallelic non\u2010truncating variants reported a significantly higher prevalence and earlier diagnosis of MH and proteinuria than individuals with monoallelic truncating variants. Individuals with biallelic variants were more severely affected than those with monoallelic variants. Those with biallelic truncating variants were more severely affected than those with compound heterozygous non\u2010truncating\/truncating variants or individuals with biallelic non\u2010truncating variants. In this study an association of heterozygous non\u2010truncating <jats:italic>COL4A3<\/jats:italic>\/<jats:italic>COL4A4<\/jats:italic> variants with a more severe phenotype in comparison to truncating variants could be shown indicating a potential dominant\u2010negative effect as an explanation for this observation. The results for individuals with ARAS support the, still scarce, data in the literature.<\/jats:p>","DOI":"10.1111\/cge.14471","type":"journal-article","created":{"date-parts":[[2024,1,12]],"date-time":"2024-01-12T11:38:12Z","timestamp":1705059492000},"page":"406-414","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Is there a dominant\u2010negative effect in individuals with heterozygous disease\u2010causing variants in <i>COL4A3\/COL4A4<\/i>?"],"prefix":"10.1111","volume":"105","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7503-5801","authenticated-orcid":false,"given":"Korbinian M.","family":"Riedhammer","sequence":"first","affiliation":[{"name":"Institute of Human Genetics Klinikum rechts der Isar, Technical University of Munich, TUM School of Medicine and Health  Munich Germany"},{"name":"Department of Nephrology Klinikum rechts der Isar Technical University of Munich TUM School of Medicine and Health  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