{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,21]],"date-time":"2026-05-21T16:01:51Z","timestamp":1779379311310,"version":"3.53.1"},"reference-count":35,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T00:00:00Z","timestamp":1552867200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81400685"],"award-info":[{"award-number":["81400685"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2019,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Alport syndrome is an inherited renal disease caused by mutations in <jats:italic>COL4A3<\/jats:italic>, <jats:italic>COL4A4,<\/jats:italic> or <jats:italic>COL4A5<\/jats:italic> genes. Coexisting mutations in either two of the three genes in Alport patients have been reported recently. However, the effect of heterozygous mutations in <jats:italic>COL4A3<\/jats:italic> or <jats:italic>COL4A4<\/jats:italic> genes in X\u2010linked Alport syndrome (XLAS) patients is unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Using targeted next\u2010generation sequencing, six unrelated Chinese children were identified to have a combination of a pathogenic variant in <jats:italic>COL4A5<\/jats:italic> and a heterozygous mutation in <jats:italic>COL4A3<\/jats:italic> or <jats:italic>COL4A4<\/jats:italic>. They were three males and three females. Another three XLAS males each with only one pathogenic variant in <jats:italic>COL4A5 <\/jats:italic>were included. The clinical data were analyzed and compared between the males in two groups (group 1, males with a pathogenic variant in <jats:italic>COL4A5 <\/jats:italic>and a heterozygous pathogenic variant in <jats:italic>COL4A3 <\/jats:italic>or <jats:italic>COL4A4<\/jats:italic>; group 2, males with only one pathogenic variant in <jats:italic>COL4A5<\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Patients with XLAS who also had heterozygous pathogenic <jats:italic>COL4A3 <\/jats:italic>or <jats:italic>COL4A4 <\/jats:italic>variants accounted for 1% of Alport syndrome. In this study, three children showed coexisting pathogenic variants in <jats:italic>COL4A5<\/jats:italic> and <jats:italic>COL4A3<\/jats:italic>. Two children showed pathogenic variants in <jats:italic>COL4A5<\/jats:italic> and <jats:italic>COL4A4<\/jats:italic>. One child had pathogenic variants in the three <jats:italic>COL4A3\u20105<\/jats:italic> genes, in which the pathogenic variant in <jats:italic>COL4A5<\/jats:italic> was de novo and the pathogenic variants in <jats:italic>COL4A4<\/jats:italic> and <jats:italic>COL4A3<\/jats:italic> were inherited independently (in trans). The site and type of mutations in <jats:italic>COL4A5 <\/jats:italic>were similar between the two groups. It was revealed that males in group 1 presented more severe proteinuria than males in group 2 (<jats:italic>p\u00a0&lt;\u00a00.05<\/jats:italic>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The present study provides further evidence for complicated genotype in Alport syndrome. For the first time, we reported a case with three pathogenic variants in <jats:italic>COL4A5<\/jats:italic>, <jats:italic>COL4A3<\/jats:italic>, and <jats:italic>COL4A4 <\/jats:italic>genes. Moreover, we found that heterozygous pathogenic <jats:italic>COL4A3<\/jats:italic> or <jats:italic>COL4A4<\/jats:italic> variants are likely to make XLAS disease more serious.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.647","type":"journal-article","created":{"date-parts":[[2019,3,18]],"date-time":"2019-03-18T19:42:16Z","timestamp":1552938136000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Effect of heterozygous pathogenic <i>COL4A3<\/i> or <i>COL4A4<\/i> variants on patients with X\u2010linked Alport syndrome"],"prefix":"10.1002","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5599-1559","authenticated-orcid":false,"given":"Yanqin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pediatrics Peking University First Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Peking University First Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongwen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Peking University First Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Yao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Peking University First Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijie","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Peking University First Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suxia","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Electron Microscopy Peking University First Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Peking University First Hospital Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2019,3,18]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2011.164"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.2349482"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12919"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12258"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.34.4.326"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/ndt\/gfn129"},{"key":"e_1_2_7_8_1","first-page":"916","article-title":"Advances and unmet needs in genetic, basic and clinical science in Alport syndrome: Report from the 2015 International Workshop on Alport Syndrome","volume":"32","author":"Gross O.","year":"2017","journal-title":"Nephrology, Dialysis, Transplantation"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ki.2013.479"},{"key":"e_1_2_7_10_1","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1681\/ASN.V114649","article-title":"X\u2010linked Alport syndrome: Natural history in 195 families and genotype\u2014phenotype correlations in males","volume":"11","author":"Jais J. 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