Further delineation of the SCAF4-associated neurodevelopmental disorder

Cosima M Schmid ^1 2, Anne Gregor ^1 2, Anna Ruiz ³, Carmen Manso Bazús ³, Isabella Herman ^4 5 6, Farah Ammouri ⁷, Urania Kotzaeridou ⁸, Vanda McNiven ⁹, Lucie Dupuis ¹⁰, Katharina Steindl ¹¹, Anaïs Begemann ¹¹, Anita Rauch ¹¹, Aude-Annick Suter ¹¹, Bertrand Isidor ¹², Sandra Mercier ¹², Mathilde Nizon ¹², Benjamin Cogné ¹², Wallid Deb ¹², Thomas Besnard ¹², Tobias B Haack ^13 14, Ruth J Falb ¹³, Amelie J Müller ¹³, Tobias Linden ¹⁵, Chad R Haldeman-Englert ¹⁶, Charlotte W Ockeloen ¹⁷, Francesca Mattioli ¹⁸, Alexandre Reymond ¹⁸, Nazia Ibrahim ¹⁹, Shagufta Naz ¹⁹, Elodie Lacaze ²⁰, Jennifer A Bassetti ²¹, Julia Hoefele ²², Theresa Brunet ²², Korbinian M Riedhammer ^22 23, Houda Z Elloumi ²⁴, Richard Person ²⁴, Fanggeng Zou ²⁴, Juliette J Kahle ²⁴, Kirsten Cremer ²⁵, Axel Schmidt ²⁵, Marie-Ange Delrue ²⁶, Pedro M Almeida ²⁷, Fabiana Ramos ^27 28, Siddharth Srivastava ²⁹, Aisling Quinlan ²⁹, Stephen Robertson ³⁰, Eva Manka ³¹, Alma Kuechler ³², Stephanie Spranger ³³, Malgorzata J M Nowaczyk ³⁴, Reem M Elshafie ³⁵, Hind Alsharhan ^35 36, Paul R Hillman ³⁷, Leslie A Dunnington ³⁷, Hilde M H Braakman ³⁸, Shane McKee ³⁹, Angelica Moresco ⁴⁰, Andrea-Diana Ignat ⁴⁰, Ruth Newbury-Ecob ⁴¹, Guillaume Banneau ⁴², Olivier Patat ⁴², Jeffrey Kuerbitz ^6 43, Susan Rzucidlo ⁴⁴, Susan S Sell ⁴⁴, Patricia Gordon ⁴⁴, Sarah Schuhmann ⁴⁵, André Reis ^45 46, Yosra Halleb ⁴⁷, Radka Stoeva ⁴⁷, Boris Keren ⁴⁸, Zainab Al Masseri ⁴⁹, Zeynep Tümer ^50 51, Sophia Hammer-Hansen ⁵², Sofus Krüger Sølyst ⁵², Connolly G Steigerwald ⁵³, Nicolas J Abreu ⁵³, Helene Faust ⁵⁴, Amica Müller-Nedebock ⁵⁴, Frédéric Tran Mau-Them ^55 56, Heinrich Sticht ⁵⁷, Christiane Zweier ^58 59

. 2024 Dec 12.

 doi: 10.1038/s41431-024-01760-2. Online ahead of print.

• PMID: 39668183
• DOI: 10.1038/s41431-024-01760-2

Abstract

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.