{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T13:30:21Z","timestamp":1786627821687,"version":"build-2736575974"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T00:00:00Z","timestamp":1678492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,6,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Von Hippel\u2013Lindau (VHL) disease is an autosomal dominant, inherited syndrome with variants in the VHL gene, causing predisposition to multi-organ neoplasms with vessel abnormality. Germline variants in VHL can be detected in 80\u201390% of patients clinically diagnosed with VHL disease. Here, we summarize the results of genetic tests for 206 Japanese VHL families, and elucidate the molecular mechanisms of VHL disease, especially in variant-negative unsolved cases. Of the 206 families, genetic diagnosis was positive in 175 families (85%), including 134 families (65%) diagnosed by exon sequencing (15 novel variants) and 41 (20%) diagnosed by multiplex ligation-dependent probe amplification (MLPA) (one novel variant). The deleterious variants were significantly enriched in VHL disease Type 1. Interestingly, five synonymous or non-synonymous variants within exon 2 caused exon 2 skipping, which is the first report of exon 2 skipping caused by several missense variants. Whole genome and target deep sequencing analysis were performed for 22 unsolved cases with no variant identified and found three cases with VHL mosaicism (variant allele frequency: 2.5\u201322%), one with mobile element insertion in the VHL promoter region, and two with a pathogenic variant of BAP1 or SDHB. The variants associated with VHL disease are heterogeneous, and for more accuracy of the genetic diagnosis of VHL disease, comprehensive genome and DNA\/RNA analyses are required to detect VHL mosaicism, complicated structure variants and other related gene variants.<\/jats:p>","DOI":"10.1093\/hmg\/ddad039","type":"journal-article","created":{"date-parts":[[2023,3,11]],"date-time":"2023-03-11T12:26:19Z","timestamp":1678537579000},"page":"2046-2054","source":"Crossref","is-referenced-by-count":14,"title":["Variant spectrum of von Hippel\u2013Lindau disease and its genomic heterogeneity in Japan"],"prefix":"10.1093","volume":"32","author":[{"given":"Kenji","family":"Tamura","sequence":"first","affiliation":[{"name":"Kochi University Department of Urology, Kochi Medical School, , Nankoku, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kanazashi","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chiaki","family":"Kawada","sequence":"additional","affiliation":[{"name":"Kochi University Department of Urology, Kochi Medical School, , Nankoku, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuya","family":"Sekine","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"},{"name":"Akita University Graduate School of Medicine Department of Urology, , Akita 010-8543, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuhiro","family":"Maejima","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shingo","family":"Ashida","sequence":"additional","affiliation":[{"name":"Kochi University Department of Urology, Kochi Medical School, , Nankoku, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Karashima","sequence":"additional","affiliation":[{"name":"Kochi University Department of Urology, Kochi Medical School, , Nankoku, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Kojima","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickolas F","family":"Parrish","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunichi","family":"Kosugi","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chikashi","family":"Terao","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shota","family":"Sasagawa","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Fujita","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Todd A","family":"Johnson","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihide","family":"Momozawa","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiji","family":"Inoue","sequence":"additional","affiliation":[{"name":"Kochi University Department of Urology, Kochi Medical School, , Nankoku, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Shuin","sequence":"additional","affiliation":[{"name":"Kochi University Department of Urology, Kochi Medical School, , Nankoku, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidewaki","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"RIKEN Center for Integrative Medical Sciences , Yokohama, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,3,11]]},"reference":[{"key":"2023060913453933800_ref1","doi-asserted-by":"crossref","first-page":"2059","DOI":"10.1016\/S0140-6736(03)13643-4","article-title":"von Hippel-Lindau 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Med. Genet."},{"key":"2023060913453933800_ref3","first-page":"521","article-title":"Genetic analysis of von Hippel-Lindau disease","volume":"31","author":"Nordstrom-O'Brien","year":"2010","journal-title":"Hum. Mutat."},{"key":"2023060913453933800_ref4","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1093\/hmg\/ddac066","article-title":"Elongin C (ELOC\/TCEB1)-associated von Hippel-Lindau disease","volume":"31","author":"Andreou","year":"2022","journal-title":"Hum. Mol. Genet."},{"key":"2023060913453933800_ref5","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1126\/science.1059817","article-title":"HIF alpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing","volume":"292","author":"Ivan","year":"2001","journal-title":"Science"},{"key":"2023060913453933800_ref6","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1126\/science.1059796","article-title":"Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2 regulated prolyl hydroxylation","volume":"292","author":"Jaakkola","year":"2001","journal-title":"Science"},{"key":"2023060913453933800_ref7","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1038\/nature04871","article-title":"Hypoxia signalling in cancer and approaches to enforce tumour regression","volume":"441","author":"Pouyss\u00e9gur","year":"2006","journal-title":"Nature"},{"key":"2023060913453933800_ref8","doi-asserted-by":"crossref","first-page":"5491","DOI":"10.1158\/0008-5472.CAN-16-0473","article-title":"A small-molecule antagonist of HIF2\u03b1 is efficacious in preclinical models of renal cell carcinoma","volume":"76","author":"Wallace","year":"2016","journal-title":"Cancer Res."},{"key":"2023060913453933800_ref9","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1038\/nature19795","article-title":"On-target efficacy of a HIF-2\u03b1 antagonist in preclinical kidney cancer models","volume":"539","author":"Cho","year":"2016","journal-title":"Nature"},{"key":"2023060913453933800_ref10","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nature19796","article-title":"Targeting renal cell carcinoma with a HIF-2 antagonist","volume":"539","author":"Chen","year":"2016","journal-title":"Nature"},{"key":"2023060913453933800_ref11","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/(SICI)1096-8628(19991119)87:2<163::AID-AJMG7>3.0.CO;2-A","article-title":"Two distinct phenotypes caused by two different missense mutations in the same codon of the VHL gene","volume":"87","author":"Bradley","year":"1999","journal-title":"Am. J. Med. Genet."},{"key":"2023060913453933800_ref12","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1186\/s12881-020-0976-7","article-title":"Case report: a synonymous VHL mutation (c.414A\u2009&gt;\u2009G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing","volume":"21","author":"Liu","year":"2020","journal-title":"BMC Med Genet."},{"key":"2023060913453933800_ref13","doi-asserted-by":"crossref","first-page":"3826","DOI":"10.1210\/jc.2019-00235","article-title":"A synonymous VHL variant in exon 2 confers susceptibility to familial pheochromocytoma and von Hippel-Lindau disease","volume":"104","author":"Flores","year":"2019","journal-title":"J. Clin. Endocrinol. 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Genet."},{"key":"2023060913453933800_ref28","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1182\/blood-2018-03-838235","article-title":"Identification of a new VHL exon and complex splicing alterations in familial erythrocytosis or von Hippel-Lindau disease","volume":"132","author":"Lenglet","year":"2018","journal-title":"Blood"},{"key":"2023060913453933800_ref29","doi-asserted-by":"crossref","first-page":"752","DOI":"10.1136\/jmedgenet-2019-106519","article-title":"Germline mutations in the new E1' cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma","volume":"57","author":"Buffet","year":"2020","journal-title":"J. Med. Genet."}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddad039\/49806904\/ddad039.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/12\/2046\/50523763\/ddad039.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/hmg\/article-pdf\/32\/12\/2046\/50523763\/ddad039.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,9]],"date-time":"2023-06-09T14:59:30Z","timestamp":1686322770000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/32\/12\/2046\/7076181"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,3,11]]},"references-count":29,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2023,3,11]]},"published-print":{"date-parts":[[2023,6,5]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddad039","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,6,12]]},"published":{"date-parts":[[2023,3,11]]}}}