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Here, we describe two children with moyamoya disease who also demonstrated kidney disease, elevated aminotransferases, and recurrent skin lesions found by exome sequencing to have de novo missense variants in <jats:italic>RNF213<\/jats:italic>. These cases highlight the ability of <jats:italic>RNF213<\/jats:italic> to cause Mendelian moyamoya disease in addition to acting as a genetic susceptibility locus. The cases also suggest a new, multi\u2010organ <jats:italic>RNF213<\/jats:italic>\u2010spectrum disease characterized by liver, skin, and kidney pathology in addition to severe moyamoya disease caused by heterozygous, de novo C\u2010terminal <jats:italic>RNF213<\/jats:italic> missense variants.<\/jats:p>","DOI":"10.1002\/ajmg.a.62215","type":"journal-article","created":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T18:43:01Z","timestamp":1620499381000},"page":"2168-2174","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["A new syndrome of moyamoya disease, kidney dysplasia, aminotransferase elevation, and skin disease associated with\u00a0de novo variants in <scp><i>RNF213<\/i><\/scp>"],"prefix":"10.1002","volume":"185","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9261-244X","authenticated-orcid":false,"given":"Alanna","family":"Strong","sequence":"first","affiliation":[{"name":"Division of Human Genetics 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