Infantile Epileptic Spasm Syndrome Caused by TAF1 Missense Variants: Expanding the Epileptic Phenotype and Revealing Underlying Impairments in Neuronal Excitability and Development

Abstract

Background Pathogenic variants in TAF1 have previously been associated with X‐linked intellectual disability and X‐linked dystonia‐parkinsonism. Epilepsy is observed in approximately 24.4% of affected individuals, ranging from focal seizures to generalized seizures including either tonic‐clonic, tonic, myoclonic, atonic or absences. To date, no cases of infantile epileptic spasm syndrome (IESS) have been associated with this neurogenetic condition. In this study, we are aimed at investigating the association between TAF1 and IESS. Methods We performed whole‐exome sequencing in two unrelated Chinese patients with IESS. Functional consequences were assessed using in vitro overexpression assays, transcriptome profiling of Neuro‐2a cells with stable TAF1 knockdown, morphological, and electrophysiological analyses in primary mouse cortical neurons. Results We identified two novel TAF1 missense variants (c.236C > A, p.T79N; c.4771G > A, p.D1591N) in the two patients. Both novel TAF1 missense variants led to reduced TAF1 protein expression, suggesting a loss‐of‐function mechanism. Transcriptome analysis revealed that TAF1 deficiency resulted in significant downregulation of key neuronal genes involved in axon guidance and epileptogenesis, including Kcnn2, Kcna4, Draxin, and Lgi1. In primary mouse cortical neurons, TAF1 knockdown markedly impaired neurite outgrowth and increased neuronal excitability. Conclusion Our findings establish TAF1 missense variants as a novel cause of IESS—a previously unrecognized phenotype—thereby expanding the epileptic phenotype of TAF1‐related disorders. Furthermore, we demonstrate that TAF1 deficiency contributes to disease pathogenesis by impairing neuronal development and increasing neuronal excitability, likely through the downregulation of Kcnn2, Kcna4, Draxin, and Lgi1.