In summary, different lines of evidence presented here support that ultra rare heterozygous and homozygous variants in STX1A cause a neurodevelopmental disorder with two different phenotypic presentations: (1) an STX1A-related developmental epileptic encephalopathy due to missense variants weakening the inhibitory STX1A-STXBP1 interaction and (2) an STX1A-related intellectual disability and autism phenotype due to inframe deletions hampering SNARE complex formation. Here, STXBP1 is linked to developmental and epileptic encephalopathy.