SCAF4 variants associated with focal epilepsy accompanied by multisystem disorders

Purpose The SCAF4 gene encodes serine/arginine-related carboxyl-terminal domain-associated factor 4, which is highly expressed in the brain and potentially affects neurodevelopment. However, the functional significance of SCAF4 variants in human diseases remains unknown. Methods Trio-based whole-exome sequencing was performed in three individuals with focal epilepsy. Bioinformatics tools were used to assess the pathogenicity of SCAF4 variants. Knockout scaf4a/b zebrafish were created using CRISPR-Cas9 used to validate the phenotype. Results SCAF4 variants were identified in three individuals from three unrelated families with focal epilepsy. All patients had focal seizures and focal discharges on EEG recordings, with intellectual disability or motor retardation, skeletal abnormalities, and one had cryptorchidism. However, no recurrence was observed after short-term ASMs treatment. The identified SCAF4 variants included two nonsense variants and one compound heterozygous variant, consisting of a missense and an in-frame variant. A low frequency of SCAF4 variants was observed in gnomAD in this study. Computational modelling has suggested that missense variants lead to functional impairments. In zebrafish, abnormal epileptiform signals, skeletal development, and neurodevelopment have been found in scaf4a/b knockout compared to wild-type zebrafish. Conclusion These results indicate that SCAF4 is associated with focal epilepsy accompanied by multisystem disorders. Otherwise, the management of patients with SCAF4 variants requires more attention to multisystem involvement.