Gene - STXBP1

Alternate gene names: RBSEC1, UNC18A, NSEC1, UNC18

Associated syndromes or conditions: Ohtahara syndrome, West syndrome, infantile epileptic encephalopathy-4

Genomic location: 9q34.1

Diagnoses observed in people with changes in the STXBP1 gene:

  • Autism Spectrum Disorder – yes
  • Intellectual Disability or Developmental Delay – yes
  • Epilepsy or Seizures – yes
  • Attention Deficit Hyperactivity Disorder – no
  • Schizophrenia – no
  • Bipolar Disorder – no

Support Resources:

  • STXBP1 Disorders: Leading the Charge Against STX Disorders: http://stxdisorders.org
    • "The STX Disorders is housed within the CHoP Foundation's Division of Neurology - STXBP1 Fund.  It  is comprised of a diverse team of families and their supports, scientists and medical professionals dedicated to ending STXBP1 Epileptic Encephalopathy. In fostering partnerships with physicians, researchers, and other foundations, we share learnings and efficiencies to increase awareness of this rare, genetic disorder and accelerate the time to finding a cure. We believe that through our work, we are leading the charge towards improved therapies and ultimately ending STXBP1 Encephalopathy. Our International STX Family has grown tremendously to 300+ united and strong and we will only continue to grow our numbers as other families have access to genetic testing."
  • STXBP1 Family Stories: 

Research Opportunities:

In addition to the opportunity to participate in research with Simons VIP, you may be interested in other opportunities.

  • WACEAN: https://wacean.com/

    • WACEAN is the latest project of the Dravet Syndrome Foundation in their effort to find better treatments for refractory epilepsy syndromes.


Infographic: https://magic.piktochart.com/output/16432455-stxbp1-infographic (share this link with others)

 


Research Article Summaries: 

Below, we've summarized several research articles that include information about STXBP1. We hope you find this information helpful! As we learn more from children who have these gene changes, we expect this list of resources and information to grow.

  • Stamberger et al. (2016) – STXBP1 encephalopathy

    The STXBP1 gene has a role in brain signaling and is most commonly linked with Ohtahara syndrome, a syndrome characterized by seizures and EEG (electroencephalograms) abnormalities presenting in infancy. As access to and uptake of genetic testing has increased, researchers have identified new gene changes (mutations) in the STXBP1 gene, allowing us to broaden our understanding of the range of features associated with STXBP1.

    In this article, Dr. Stamberger and her team identified 45 individuals with STXBP1 mutations through research and diagnostic populations. They performed a literature review of current STXBP1 research and compared the observed features in the newly-identified 45 individuals with 102 other individuals with STXBP1 mutations who were previously published in other research articles.

    Ranging from 6 months to 56 years in age, researchers compared diagnoses (see below) and features observed in the 147 individuals with STXBP1 mutations. All 147 individuals were reported as having some degree of intellectual disability (ID), with approximately 88.4% categorized as severe or profound ID. The majority of individuals (approximately 95%) were found to have an epilepsy-related diagnosis, with onset early in life, which likely prompted genetic testing in the first place. Over 60% of those diagnosed with a form of epilepsy have a history of abnormal EEGs. Autism was observed in approximately 1 in 5 individuals and impaired or delayed motor functioning were frequently reported.

 

  • Gburek-Augustat et al. (2016) – Epilepsy is not a mandatory feature of STXBP1 associated ataxia-tremor-retardation syndrome

    The STXBP1 gene is associated with signaling pathways in the brain, and in the past, genetic changes (mutations) in the STXBP1 gene were commonly associated with early infantile epileptic encephalopathy (EIEE), an epileptic condition characterized by frequent seizures and spikes in EEGs (electroencephalograms) within the first few months of life. This condition is referred to as Ohtahara syndrome. Over time, changes in the STXBP1 gene were recognized in individuals with other forms of epilepsy, as well as in individuals with intellectual disability (ID) and movement disorders without a history of epilepsy.

    This recent study by the Gburek-Augustat research team identified three unrelated females (“Patient I”: age 12, “Patient II”: age 11, and “Patient III”: age 9). with de novo STXBP1 mutations, meaning their mutations were not found to be inherited from their parents. Patient I was identified through whole-exome sequencing; Patient II was identified using a ID genetic testing panel; and Patient III was referred to the researchers by Patient II’s parents because of their similar features. All three girls had ID and severe developmental delay (DD), as well as similar clinical features. While no epilepsy or abnormal brain MRIs or EEGs were reported in any of the patients, the following features were reported in all three patients: ID, DD, low muscle tone (hypotonia), psychomotor delay, action tremors of arms and hands, coordination issues (ataxia), and limited speech abilities. Interestingly, the ID and DD reported in each patient was not as severe as individuals who do have EIEE.

    Previously, the STXBP1 gene was primarily considered as a potential diagnosis for patients with epilepsy. While most individuals found to have a mutation in STXBP1 do have epilepsy, this research shows that it is possible for changes in this gene to be found in individuals without epilepsy. This suggests that that epilepsy should not be considered a mandatory feature of individuals with a STXBP1 mutation and that testing should be expanded and performed in those individuals who have ID/DD, hypotonia, language issues, ataxia, and tremors without epilepsy.

    New technologies and research are helping us learn more about genetic diseases, causes, and symptoms every day. Many of these developments would not be possible without participation in research projects. Thank you to our Simons VIP families who are allowing us to gain more information on genetic changes that may lead to future developments of our own!

     

  • Carvill et al. (2014)GABRA1 and STXBP1: Novel genetic causes of Dravet syndrome

    Dravet Syndrome is an infantile-onset epilepsy disorder that is associated with developmental delays, intellectual disability, and different types of seizures later in life, and is caused by genetic changes (mutations) in the SCN1A gene in about 75% of patients.

    Carvill and her team performed whole-exome sequencing (WES) in thirteen individuals who did not have an SCN1A mutation, but were diagnosed with Dravet Syndrome. Of these thirteen individuals, three were found to have de novo (not found in either parent) mutations in the STXBP1 gene.

    All three individuals had an onset of Dravet Syndrome within their first year of life, although at a later age (6-12 months) than what is usually seen in individuals with STXBP1, where onset is usually by 3 months. Two had a history of both tonic and atonic seizures, both of which are rare in the early stages of Dravet Syndrome, and all three were not observed to have epileptic spasms, which are often associated with having STXBP1. Two of the patients had severe intellectual disability (ID), while one had learning difficulties. Based on their findings, the researchers suggest that STXBP1 contributes to Dravet Syndrome and should be considered for genetic testing in cases where and SCN1A mutation is not found.

     

    ·         Hamdan et al. (2011)Intellectual disability without epilepsy associated with STXBP1 disruption

    Following up on their previous research (Hamdan et al., 2009), Dr. Hamdan and his team sequenced samples from 50 new individuals with non-syndromic intellectual disability (NSID). They identified one 21-year-old individual with a de novo mutation (not found in either parent) in the STXBP1 gene. Unlike their previous findings (where two individuals were reported to have non-specific epilepsy were found to have STXBP1 mutations), the newly identified individual did not have a reported history of epilepsy. He was reported to have a diagnosis of severe intellectual disability (ID), but had no history abnormal EEGs or brain imaging. The individual did not experience any muscle weakness (hypotonia), but did have a history of tremors. This finding supports the idea that the STXBP1 gene may be linked to a wider range or spectrum of features than previously understood.

     

    ·         Hamdan et al. (2009)De novo STXBP1 mutations in mental retardation and nonsyndromic epilepsy

    Genetic testing (exome or panel sequencing) was completed for 95 individuals diagnosed with intellectual disability (ID), without growth abnormalities or specific dysmorphic features. From this group of 95 patients, researchers were able to identify 2 de novo mutations (gene changes not found in either parent) in the STXBP1 gene. Both patients were reported to be diagnosed with severe ID, epilepsy (with the first seizures occurring at 6 weeks of age and at almost 3 years of age, respectively), muscle weakness (hypotonia) and tremors. Brain imaging for both individuals was reported as normal. Later, the study expanded to include sequencing results from 142 individuals with autism spectrum disorder (ASD) as well as 190 health individuals. No STXBP1 mutations were found in either of these groups, suggesting that mutations in STXBP1 are associated with ID and non-syndromic epilepsy.

     

 


 

You can also visit SFARI's website to see information for researchers about this gene. SFARIgene: STXBP1

 

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