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We assembled data on 50 novel individuals with <jats:italic>SCAF4<\/jats:italic> variants ascertained via GeneMatcher and personal communication. With detailed evaluation of clinical data, in silico predictions and structural modeling, we further characterized the molecular and clinical spectrum of the autosomal dominant <jats:italic>SCAF4<\/jats:italic>-associated neurodevelopmental disorder. The molecular spectrum comprises 25 truncating, eight splice-site and five missense variants. While all other truncating variants were classified as pathogenic\/likely pathogenic, significance of one C-terminal truncating variant, one splice-site variant and the missense variants remained unclear. Three missense variants in the CTD-interacting domain of SCAF4 were predicted to destabilize the domain. Twenty-three variants occurred de novo, and variants were inherited in 13 cases. Frequent clinical findings were mild developmental delay with speech impairment, seizures, and skeletal abnormalities such as clubfoot, scoliosis or hip dysplasia. Cognitive abilities ranged from normal IQ to severe intellectual disability (ID), with borderline to mild ID in the majority of individuals. Our study confirms the role of <jats:italic>SCAF4<\/jats:italic> variants in neurodevelopmental disorders and further delineates the associated clinical phenotype.<\/jats:p>","DOI":"10.1038\/s41431-024-01760-2","type":"journal-article","created":{"date-parts":[[2024,12,12]],"date-time":"2024-12-12T06:18:11Z","timestamp":1733984291000},"page":"588-594","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Further delineation of the SCAF4-associated neurodevelopmental disorder"],"prefix":"10.1038","volume":"33","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-5562-199X","authenticated-orcid":false,"given":"Cosima 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