{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T21:43:12Z","timestamp":1792014192416,"version":"4.4.0"},"reference-count":55,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T00:00:00Z","timestamp":1660176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"2018-22 EU Research","award":["H2020-HEALTH-SC1-2017-RTD"],"award-info":[{"award-number":["H2020-HEALTH-SC1-2017-RTD"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband\u2019s carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118\u20134122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.<\/jats:p>","DOI":"10.3390\/ijms23168952","type":"journal-article","created":{"date-parts":[[2022,8,11]],"date-time":"2022-08-11T21:15:05Z","timestamp":1660252505000},"page":"8952","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense RNF213 Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4547-0500","authenticated-orcid":false,"given":"Claudia","family":"Santoro","sequence":"first","affiliation":[{"name":"Child and Adolescent Neuropsychiatry Clinic, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Pansini 5, 80131 Naples, Italy"},{"name":"Department of Women\u2019s and Children\u2019s Health, and General and Specialized Surgery, University of Campania \u201cLuigi Vanvitelli\u201d, Via De Crecchio 4, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Mirone","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Santobono-Pausilipon Children\u2019s Hospital, AORN, Via Ravaschieri 8, 80122 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3750-1592","authenticated-orcid":false,"given":"Mariateresa","family":"Zanobio","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi De Crecchio 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giusy","family":"Ranucci","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Santobono-Pausilipon Children\u2019s Hospital, AORN, Via Ravaschieri 8, 80122 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandra","family":"D\u2019Amico","sequence":"additional","affiliation":[{"name":"Department of Radiology, Tortorella Private Hospital, Via Aversano 1, 84214 Salerno, 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Ravaschieri 8, 80122 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7798-4368","authenticated-orcid":false,"given":"Vincenzo","family":"Piccolo","sequence":"additional","affiliation":[{"name":"Dermatology Unit, University of Campania \u201cLuigi Vanvitelli\u201d, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ronchi","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Unit, University of Campania \u201cLuigi Vanvitelli\u201d, Piazza Miraglia 2, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Limongelli","sequence":"additional","affiliation":[{"name":"Division of Cardiology, Monaldi Hospital, University of Campania \u201cLuigi Vanvitelli\u201d, Via Bianchi, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8136-7597","authenticated-orcid":false,"given":"Marco","family":"Carotenuto","sequence":"additional","affiliation":[{"name":"Child and Adolescent Neuropsychiatry Clinic, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Pansini 5, 80131 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincenzo","family":"Nigro","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi De Crecchio 7, 80138 Naples, Italy"},{"name":"Telethon Institute of Genetics and Medicine, Via Campi Flegrei 34, 80078 Pozzuoli, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7797-8483","authenticated-orcid":false,"given":"Giuseppe","family":"Cinalli","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, Santobono-Pausilipon Children\u2019s Hospital, AORN, Via Ravaschieri 8, 80122 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9418-125X","authenticated-orcid":false,"given":"Giulio","family":"Piluso","sequence":"additional","affiliation":[{"name":"Department of Precision Medicine, University of Campania \u201cLuigi Vanvitelli\u201d, Via Luigi De Crecchio 7, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1226","DOI":"10.1056\/NEJMra0804622","article-title":"Moyamoya disease and moyamoya 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