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We reported that the pathogenic variant c.1617del of <jats:italic>TMEM260<\/jats:italic>, which encodes a transmembrane protein, is highly associated with CHD, specifically persistent truncus arteriosus (PTA), the most severe cardiac outflow tract (OFT) defect. Using whole-exome sequencing, the c.1617del variant was identified in two siblings with PTA in a Japanese family and in three of the 26 DNAs obtained from Japanese individuals with PTA. The c.1617del of <jats:italic>TMEM260<\/jats:italic> has been found only in East Asians, especially Japanese and Korean populations, and the frequency of this variant in PTA is estimated to be next to that of the 22q11.2 deletion, the most well-known genetic cause of PTA. Phenotype of patients with c.1617del appears to be predominantly in the heart, although <jats:italic>TMEM260<\/jats:italic> is responsible for structural heart defects and renal anomalies syndrome (SHDRA). The mouse TMEM260 variant (p.W535Cfs*56), synonymous with the human variant (p.W539Cfs*9), exhibited truncation and downregulation by western blotting, and aggregation by immunocytochemistry. In situ hybridization demonstrated that <jats:italic>Tmem260<\/jats:italic> is expressed ubiquitously during embryogenesis, including in the development of cardiac OFT implicated in PTA. This expression may be regulated by a\u2009~\u20090.8\u2009kb genomic region in intron 3 of <jats:italic>Tmem260<\/jats:italic> that includes multiple highly conserved binding sites for essential cardiac transcription factors, thus revealing that the c.1617del variant of <jats:italic>TMEM260<\/jats:italic> is the major single-gene variant responsible for PTA in the Japanese population.<\/jats:p>","DOI":"10.1038\/s10038-024-01225-w","type":"journal-article","created":{"date-parts":[[2024,2,26]],"date-time":"2024-02-26T07:02:16Z","timestamp":1708930936000},"page":"215-222","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["The c.1617del variant of TMEM260 is identified as the most frequent single gene determinant for Japanese patients with a specific type of congenital heart disease"],"prefix":"10.1038","volume":"69","author":[{"given":"Tadashi","family":"Inoue","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuta","family":"Takase","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9249-6345","authenticated-orcid":false,"given":"Keiko","family":"Uchida","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Kodo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Suda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4685-8021","authenticated-orcid":false,"given":"Yoriko","family":"Watanabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3209-5780","authenticated-orcid":false,"given":"Koh-Ichiro","family":"Yoshiura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masaya","family":"Kunimatsu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reina","family":"Ishizaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenko","family":"Azuma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Inai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Muneuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshiyuki","family":"Furutani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7791-7384","authenticated-orcid":false,"given":"Hiroyuki","family":"Akagawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yamagishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,2,26]]},"reference":[{"key":"1225_CR1","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1093\/ije\/dyz009","volume":"48","author":"Y Liu","year":"2019","unstructured":"Liu Y, Chen S, Z\u00fc L, Black GC, Choy M-K, Li N, et al. 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Clinical evaluations were approved by the Internal Ethics Committee of Keio University School of Medicine (approval number 20170043), Tokyo Women\u2019s Medical University (approval number 313E), and Kurume University School of Medicine (approval number 265) and were conducted only after written informed consent was obtained. All animal experiments were approved by the Institutional Animal Care and Use Committee of Keio University (approval number 09122) and conformed to the National Institutes of Health Guidelines for the Care and Use of Laboratory Animals. All genetic modification protocols were approved by the Genetic Modification Safety Committee, Keio University School of Medicine (approval number D2005\u2013002), and the experiments were safely conducted in compliance with the \u201cLaw Concerning Conservation of Biological Diversity through Regulations on Use of Living Modified Organisms\u201d and related government ordinances and notifications.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}]}}