Novel Splice Site Pathogenic Variant in STXBP1 Gene in a Child with Intellectual Disability, Epilepsy, and Autism Spectrum Disorder: A Case Report

Abstract Introduction: Pathogenic variants in the STXBP1 gene are associated to a large spectrum of severe early onset developmental and epileptic encephalopathies (OMIM #612164). They were also identified in various other neurodevelopmental disorders. This gene encodes for the syntaxin-binding protein 1, a member of the SEC-1 family of membrane-transport proteins that modulate the presynaptic vesicular fusion by interacting with soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs). However, the physiopathology of STXBP1 pathogenic variants is not yet fully understood. Case Presentation: Herein, we report a patient presenting intellectual disability, early onset seizures, and autism. Clinical exome sequencing identified a novel monoallelic splice pathogenic variant STXBP1(NM_001032221.6):c.38–2A>G. Discussion: Splice-site pathogenic variants in the STXBP1 gene are mostly associated with West syndrome, early onset epilepsy and encephalopathy, and Ohtahara syndrome. Our findings extend clinical and molecular spectrum of STXBP1 gene variants by reporting the first splice-site variant associated with autism along with early onset epilepsy and, and intellectual disability in a patient. Established FactsSTXBP1 pathogenic variants are associated with a large spectrum of neurodevelopmental disorders, mainly early onset developmental and epileptic encephalopathies.43 STXBP1 splice-site variants are reported in literature. 28% are associated with West syndrome, 23% with early onset epilepsy and encephalopathy, and 18% Ohtahara syndrome. None of them is associated with autistic spectrum disorder.Autism spectrum disorder is found in 2% of cases with missense variants, 2% of cases with nonsense variants, and 5% of cases with frameshift variants.