Schmid CM, Gregor A, Ruiz A, Manso Bazús C, Herman I, Ammouri F, Kotzaeridou U, McNiven V, Dupuis L, Steindl K, Begemann A, Rauch A, Suter AA, Isidor B, Mercier S, Nizon M, Cogné B, Deb W, Besnard T, Haack TB, Falb RJ, Müller AJ, Linden T, Haldeman-Englert CR, Ockeloen CW, Mattioli F, Reymond A, Ibrahim N, Naz S, Lacaze E, Bassetti JA, Hoefele J, Brunet T, Riedhammer KM, Elloumi HZ, Person R, Zou F, Kahle JJ, Cremer K, Schmidt A, Delrue MA, Almeida PM, Ramos F, Srivastava S, Quinlan A, Robertson S, Manka E, Kuechler A, Spranger S, Nowaczyk MJM, Elshafie RM, Alsharhan H, Hillman PR, Dunnington LA, Braakman HMH, McKee S, Moresco A, Ignat AD, Newbury-Ecob R, Banneau G, Patat O, Kuerbitz J, Rzucidlo S, Sell SS, Gordon P, Schuhmann S, Reis A, Halleb Y, Stoeva R, Keren B, Al Masseri Z, Tümer Z, Hammer-Hansen S, Krüger Sølyst S, Steigerwald CG, Abreu NJ, Faust H, Müller-Nedebock A, Tran Mau-Them F, Sticht H, and Zweier C
While mostly de novo truncating variants in SCAF4 were recently identified in 18 individuals with variable neurodevelopmental phenotypes, knowledge on the molecular and clinical spectrum is still limited. We assembled data on 50 novel individuals with SCAF4 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 SCAF4-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 SCAF4 variants in neurodevelopmental disorders and further delineates the associated clinical phenotype., Competing Interests: Competing interests: HZE, RP, FZ and JK are employees of GeneDx, LLC. The remaining authors declare no conflicts of interest. Ethics: The research protocol fulfilled the requirements of the local institutional ethics committee (Kantonale Ethikkommission Bern, 2021-01396). Consent for publication of genetic and clinical data, as well as photographs was obtained from the individuals, their parents, or legal guardians, respectively. The study complied with the principles set out in the Declaration of Helsinki., (© 2024. The Author(s).)