{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T04:53:20Z","timestamp":1791003200458,"version":"4.1.0"},"reference-count":50,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Higher Education of the Russian Federation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Von Hippel\u2013Lindau syndrome (VHLS) is an autosomal dominant hereditary cancer disease caused by germline mutations in the VHL tumor suppressor gene and characterized by clinical heterogeneity and phenotype\u2013genotype associations. We studied the VHL gene in 535 Russian patients referred for VHLS diagnostics using Sanger sequencing, multiplex ligase-dependent probe amplification, and, in some cases, high-throughput sequencing. A total of 177 causative VHL variants were identified, including 129 point mutations and 48 extended deletions. Missense variants were the most frequent (60.3%) and predominantly localized at codons 167, 88, and 78. Approximately 88% of the analyzed missense variants and in-frame indels led to changes directly at the HIF-\u03b1- and ELOC-binding sites of pVHL. Patients with causative VHL variants had CNS hemangioblastoma (69.7%), retinal hemangioblastomas (41.4%), clear-cell renal carcinoma (CCRC) (27.3%), renal cysts (22.2%), pancreatic cysts (20.2%), and pheochromocytoma (7.1%). The frequency of multiple pathological changes in targeted organs was significantly higher in patients with causative variants than in the group without mutations, at 78.8% versus 21.1% (p &lt; 0.0001), whereas a single case of CCRC, even in adults under 60 years of age, had a low positive predictive value (14.7%) in relation to P\/LP variant detection. The variant c.208G&gt;A;p.Glu70Lys was identified in four patients of East Asian ancestry only; the nonsense variant c.481C&gt;T;p.Arg161* was found significantly more frequently in patients of Turkic ethnicities than in Slavic patients: 30.0 versus 2.5% (p = 0.0047). We did not identify significant differences in the profile of causative germline variants and frequencies of various VHLS clinical manifestations in our cohort compared with other Slavic people. Also, we examined 87 relatives of probands and identified 41 carriers of the causative variants. The obtained results may contribute to improving the diagnosis of VHLS.<\/jats:p>","DOI":"10.3390\/ijms27198804","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T10:25:44Z","timestamp":1790850344000},"page":"8804","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical and Genetic Characterization of Russian Patients with von Hippel\u2013Lindau Syndrome"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9780-8708","authenticated-orcid":false,"given":"Dmitry S.","family":"Mikhaylenko","sequence":"first","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"},{"name":"Department of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"software","vocabulary":"credit"}]},{"given":"Natalya N.","family":"Vasserman","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"software","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-8108-2824","authenticated-orcid":false,"given":"Natalya B.","family":"Kuryakova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"resources","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5825-0430","authenticated-orcid":false,"given":"Ekaterina B.","family":"Kuznetsova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"},{"name":"Department of Translational Medicine and Biotechnology, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Nina A.","family":"Gorban","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"},{"name":"A.F. Tsyb Medical Radiological Research Center\u2014Branch of the National Medical Research Center of Radiology, Obninsk 249036, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0416-8137","authenticated-orcid":false,"given":"Anna A.","family":"Stepanova","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4905-1303","authenticated-orcid":false,"given":"Olga A.","family":"Shchagina","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Alexander V.","family":"Polyakov","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"project-administration","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9323-2673","authenticated-orcid":false,"given":"Dmitry V.","family":"Zaletaev","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"project-administration","vocabulary":"credit"}]},{"given":"Sergey I.","family":"Kutsev","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9283-902X","authenticated-orcid":false,"given":"Vladimir V.","family":"Strelnikov","sequence":"additional","affiliation":[{"name":"Research Centre for Medical Genetics, Moscow 115522, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"conceptualization","vocabulary":"credit"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"ref_1","first-page":"e70090","article-title":"Global cancer statistics 2024: GLOBOCAN estimates of incidence and mortality worldwide for 34 cancers in 186 countries","volume":"76","author":"Sung","year":"2026","journal-title":"CA Cancer J. 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