Heterozygous and homozygous variants in STX1A cause a neurodevelopmental disorder with or without epilepsy.

Scientists studied 8 people with rare changes in a gene called STX1A that affects brain development. They found these genetic changes cause different problems depending on the type of change: some mainly cause seizures, while others mainly cause intellectual disability and autism-like behaviors. This helps doctors understand how problems with brain cell communication can lead to different developmental conditions.

This case series describes eight individuals with ultra-rare variants in the STX1A gene, presenting with neurodevelopmental disorders including intellectual disability, autism, and epilepsy. The study identifies two distinct pathogenic mechanisms based on variant type: missense variants primarily causing epilepsy through weakened STX1A-STXBP1 protein interactions, and single amino acid deletions/splice variants causing intellectual disability and autistic behaviors through impaired SNARE complex formation. The researchers propose this represents a new category of rare genetic disorders called STX1A-related SNAREopathies, expanding understanding of synaptic protein dysfunction in neurodevelopment.

Identifies STX1A as a new gene associated with neurodevelopmental disorders. Suggests variant-specific clinical trajectories may inform prognosis and management approaches. Expands genetic testing panels for individuals with unexplained intellectual disability, autism, or epilepsy.

Very small sample size of only 8 individuals limits generalizability. Case series design without controls provides limited evidence strength. In silico modeling predictions require experimental validation.

The neuronal SNARE complex drives synaptic vesicle exocytosis. Therefore, one of its core proteins syntaxin 1A (STX1A) has long been suspected to play a role in neurodevelopmental disorders. We assembled eight individuals harboring ultra rare variants in STX1A who present with a spectrum of intellectual disability, autism and epilepsy. Causative variants comprise a homozygous splice variant, three de novo missense variants and two inframe deletions of a single amino acid.

We observed a phenotype mainly driven by epilepsy in the individuals with missense variants in contrast to intellectual disability and autistic behavior in individuals with single amino acid deletions and the splicing variant. In silico modeling of missense variants and single amino acid deletions show different impaired protein-protein interactions. We hypothesize the two phenotypic courses of affected individuals to be dependent on two different pathogenic mechanisms: (1) a weakened inhibitory STX1A-STXBP1 interaction due to missense variants results in an STX1A-related developmental epileptic encephalopathy and (2) a hampered SNARE complex formation due to inframe deletions causes an STX1A-related intellectual disability and autism phenotype. Our description of a STX1A-related neurodevelopmental disorder with or without epilepsy thus expands the group of rare diseases called SNAREopathies.