ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000009.11) (NC_000009.12)
Evidence for haploinsufficiency phenotype
PubMed ID Description
19557857 Hamdan et al. (2009): 95 French-Canadian individuals with sporadic intellectual disability and without growth abnormalities or specific dysmorphic features were studied. Three heterozygous changes in STXBP1 were found, including a splice junction (c.169+1G>A) and a nonsense (c.1162C>T); both of those changes were de novo. Sequencing all STXBP1 exons and intronic junctions in two control cohorts by this group (n = 190) and by the Sanger Institute's ExoSeq project (n = 48 Europeans) did not show any splicing or amino acid?altering mutations. No amino acid?altering or splicing mutations were found in the other four sequenced genes (STX1A, VAMP2, SNAP25, SYT1) in this cohort. In regards to the splice-site mutation, all the corresponding transcripts result in the insertion of seven new amino acids at position 57 followed by a premature stop codon. The individuals with these mutations both had epilepsy (though the specific type was not stated) in addition to profound intellectual disability. The same group sequenced STXBP1 in 50 additional French-Canadian individuals with sporadic intellectual disability in 2011. Hamdan et al. (2011) (PMID:21364700) describes a novel de novo truncating mutation, c.1206delT/p.402X, in a patient with severe cognitive deficit, but with no history of epilepsy. The authors conclude that the mutation is likely to be pathogenic as it is predicted to truncate STXBP1 towards the middle of its sequence, in the same functional domain as p.R388X, a mutation they reported in the article referenced above.
23409955 Weckhuysen et al. 2013: Describes six novel mutations in individuals with epileptic encephalopathies of various types, including one nonsense mutation (c.607C>T, p.Gln203*) in a 20-month-old male with a clinical diagnosis of Ohtahara syndrome. The other mutations, including missense and splice site mutations, were found in individuals with Ohtahara syndrome, West syndrome, and infantile epileptic spasms from onset without hypsarrhythmia on EEG. All were found to be de novo. None of these mutations has been registered in the 1000 Genomes Project or the Single Nucleotide Polymorphism Database and five of six were absent in 240 ethnically matched control individuals. For the patient with the nonsense mutation, an indigenous Australian, no ethnically matched controls were available.

Haploinsufficiency phenotype comments:

Of note, Saitsu et al. (2008) (PMID:18469812) describe 4 heterozygous missense mutations amongst 4 unrelated individuals with early infantile epileptic encephalopathy (EIEE, or Ohtahara syndrome). They also describe an individual with a de novo 2.0 Mb microdeletion detected on BAC array that included the STXBP1 gene (in addition to numerous others). All described individuals were said to have profound intellectual disability. The authors suggest haploinsufficiency of STXBP1 causes EIEE, as they found that a mutant form of the protein was significantly thermolabile compared to wild type in Circular dichroism melting experiments, and that binding of the mutant protein to syntaxin was impaired. Rauch et al. 2012 (PMID: 23020937) described two missense and one splice site variant detected by whole exome sequencing amongst a German cohort of individuals with nonspecific intellectual disability. All changes were de novo. The authors looked for loss-of-function mutations in roughly 1600 control exomes and did a post-hoc test in the 6500 exomes from the Exome Variant Server (version 0.0.14), and in 179 low-coverage genomes of the 1000 Genomes project.20 The Exome Variant Server dataset does not contain small deletions or insertions. No loss-of-function variants in STXBP1 were detected, supporting the likely pathogenicity of the candidate de-novo variants identified.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity