The syntaxin-binding protein 1 (STXBP1) encephalopathy represents a heterogeneous neurodevelopmental spectrum, manifesting as epileptic encephalopathies, intellectual disability, and autism-related phenotypes. It is a broad clinical entity encompassing a range of neurodevelopmental and epileptic disorders, including West syndrome, unclassified early-onset epileptic encephalopathy, Dravet syndrome, non-syndromic epilepsy, intellectual disability, autism spectrum disorder, and Rett-like syndrome. We present a case of a 4-year-old girl with global developmental delay, infantile-onset pharmacoresistant seizures, autistic features, and repetitive hand automatisms mimicking Rett syndrome. Targeted sequencing revealed a pathogenic de novo non-sense mutation in STXBP1, demonstrating striking Rett-like symptomatology without classic MECP2 mutations. The findings highlight three critical implications: (i) STXBP1 screening should be prioritized in Rett spectrum disorders with negative initial testing, (ii) hand stereotypies represent an underrecognized feature in STXBP1 encephalopathy, and (iii) precision diagnosis enables tailored therapeutic strategies and prognostic counseling. Our observations reinforce the necessity of broad genetic panels in neurodevelopmental disorders, particularly when phenotypic overlap obscures traditional diagnostic boundaries.