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However, the factors affecting its penetrance remain unclear. Therefore, our study aims to identify modifier genes associated with the incomplete penetrance of this founder mutation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Whole\u2010exome sequencing (WES) was performed on 36 participants, including 22\u2009MMD patients and 14 non\u2010MMD controls with <jats:italic>RNF213<\/jats:italic> p.R4810K mutation. Fisher's exact test was used to assess the presence of genetic variants that differed significantly between MMD patients and non\u2010MMD controls. In order to exclude false\u2010positive results, another 55 carriers were included to perform Fisher's exact test for the selected sites in the WES discovery stage. Subsequently, human brain microvascular endothelial cells were transfected with wild\u2010type and mutant <jats:italic>HAPLN3<\/jats:italic> for tube formation assays and western blotting to explore the impact of candidate genes on angiogenesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Analysis of variants from WES data revealed a total of 12 non\u2010synonymous variants. Through bioinformatics analysis, the focus was on the <jats:italic>HAPLN3<\/jats:italic> p.T34A variant with a significant <jats:italic>p<\/jats:italic> value of 0.00731 in Fisher's exact test. Validation through Sanger sequencing confirmed the presence of this variant in the WES data. In\u00a0vitro experiments revealed that silencing <jats:italic>HAPLN3<\/jats:italic> and transfecting <jats:italic>HAPLN3<\/jats:italic> p.T34A significantly enhanced tube formation and increased the relative protein expression of vascular endothelial growth factor in endothelial cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>These results suggest that <jats:italic>HAPLN3<\/jats:italic> may function as a modifier gene of <jats:italic>RNF213<\/jats:italic> p.R4810K, promoting the development of MMD and contributing to the incomplete penetrance of MMD founder mutations.<\/jats:p><\/jats:sec>","DOI":"10.1111\/ene.16473","type":"journal-article","created":{"date-parts":[[2024,9,24]],"date-time":"2024-09-24T09:27:07Z","timestamp":1727170027000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["<i>HAPLN3<\/i> p.<scp>T34A<\/scp> contributes to incomplete penetrance of moyamoya disease in Chinese carrying <i>RNF213<\/i> p.<scp>R4810K<\/scp>"],"prefix":"10.1111","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4384-7248","authenticated-orcid":false,"given":"Jun","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic Disease Control &amp; Prevention, Ministry of Education (China Medical University), Department of Nutrition and Food Hygiene, School of Public Health China Medical University  Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhengxing","family":"Zou","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, the Fifth Medical Centre Chinese PLA General Hospital  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9959-8377","authenticated-orcid":false,"given":"Wanyang","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory of Environmental Stress and Chronic 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