Novel missense variants of TAF1 are associated with infantile epileptic spasms and impaired neuronal excitability and development

Infantile epileptic spasm syndrome (IESS) is a severe type of epileptic encephalopathy with strong genetic associations. The TAF1 gene encodes the TATA-box-binding protein factor 1 protein, a critical component of transcription factor II D complex essential for initiating transcription. Missense variants of TAF1 have previously been implicated in X-linked intellectual disability. Here, we report two novel missense variants of TAF1 (c.236C > A, p.T79N; c.4771G > A, p.D1591N) linked to IESS. We investigated the role of TAF1 and its association with epileptogenesis. We showed that IESS-related TAF1 missense variants reduce protein expression in overexpression assays, suggesting a loss-of-function mechanism. Transcriptome analysis of Neuron-2a cells with stable TAF1 knockdown revealed its critical role in neurodevelopmental processes, exhibiting significant downregulation of neuronal genes (Kcnn2, Kcna4, Draxin, and Lgi1) in axon guidance and epileptogenesis. In addition, TAF1 knockdown in primary mouse cortical neurons significantly reduced neurite outgrowth and enhanced neuronal excitability. These results indicate that TAF1 deficiency can lead to epileptic encephalopathy by impairing neuronal excitability and development probably due to the downregulation of neuronal genes related to TAF1 deficiency. Our study expands the clinical spectrum of TAF1-related disorders and provides mechanistic insights into its role in epileptic encephalopathies.