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

Abstract

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.

Syntaxin1A overexpression and pain insensitivity in individuals with 7q11.23 duplication syndrome

“…Table 2 shows that a parallel can be drawn between the culture experiments and gene dosage and pain sensitivity status in humans: 1 or 2 copies of the STX1A gene in individuals with WS (+/–) or their siblings (+/+), respectively, supports adequate nociceptive functions, whereas 3 copies are inhibitory. Although the effects of a full STX1A knockout in humans are currently unknown, it likely would involve other severe phenotypic presentations ( 31 ). However, extrapolating to include the Stx1a -knockout mouse, which exhibits an increased nociceptive phenotype ( 32 ), then nociceptive responsiveness ranges from enhanced sensitivity with 0 copies (mouse), to normal with 1 or 2 copies, and inhibited with 3 copies ( Table 2 ).…”

“…Mutations in genes mediating the synaptic docking process, including STX1A , are rare. Individuals harboring mutations in STX1A have not been carefully studied for alterations in pain sensitivity, though it is interesting to note that different phenotypes occur if the mutations involve interaction with STXBP1, which normally inhibits STX1A-SNARE interactions, or the domain of STX1A that interacts directly with the other 2 members of SNARE complex ( 31 ). This raises the possibility that the inhibitory effects of overexpression of STX1A protein may vary based on genetic variation in other interacting SNARE proteins.…”

STXBP6 Gene Mutation: A New Form of SNAREopathy Leads to Developmental Epileptic Encephalopathy

“…This structure consists of two SNAP25 helices (encoded by SNAP25), one syntaxin 1A helix (encoded by the STX1A gene), and one synaptobrevin 2 helix (encoded by VAMP2) [17]. Causative variants within these genes responsible for SNARE protein synthesis encompass a wide array of genetic alterations, including homozygous splice variants, de novo missense variants, and in-frame deletions affecting only a few amino acids [18].…”

2023 in the European Journal of Human Genetics

“…Exome and genome sequencing remain critical to diagnosis of rare disease, and identification of novel genomic causes. In March 2023, Luppe et al reported mono-and bi-allelic variants in STX1A as causing a novel neurodevelopmental disorder [10]. Genome sequencing identified that copy number variants of FGF14 underlie a condition of early onset nystagmus and variable ataxia [11] while ARHGAP35 was identified as causing a range of anterior chamber malformations [12].…”