Case report: A novel STXBP1 splice variant and the landscape of splicing-involved STXBP1 -related disorders.

variants are one of the most common genetic causes of neurodevelopmental disorders and epilepsy, wherein -related disorders are characterized by neurodevelopmental abnormalities in 95% and seizures in 89% of affected patients. However, the spectrums of both genotype and phenotype are quite wide and diverse, with a high baseline variability even for recurrent variants. Until now, no clear genotype-phenotype correlations have been established and multiple disease mechanisms have been proposed for -related disorders. Without an ascertained disease cause for many cases of variants, it is challenging to manage this disease in an effective manner and current symptom-based treatments are focused on seizure control only, which has a minimal impact on global development. A novel canonical splice variant, NM_001032221.4:c.578+2T>C, was reported in this study, together with detailed documentation of disease manifestations and treatment management. Further RNA expression analysis revealed abnormal intron retention and possible production of truncated STXBP1 proteins as a likely pathogenic mechanism. More importantly, the landscape of previously understudied splice variants and functional investigations was assessed for the first time to provide a context for the discussion of the complicated genotype-phenotype relationship of -related disorders. Future cases of this disorder and a deeper mechanism-based understanding of its pathogenic cause are required for precision medicine and better disease management.