What is Syngap1?

The protein’s function is particularly important during a critical period of early brain development that affects future cognitive ability.

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What is SYNGAP1?

Children born with a SYNGAP1 gene mutation or variant, are affected by a variety of symptoms, ranging from mild to severe.

In 2009, the first SYNGAP1 patient was identified and reported in medical literature.

The SYNGAP1 gene is located in the brain and provides instructions for making a protein, called SynGAP, that plays an important role in nerve cells in the brain.

SynGAP is found at the junctions between nerve cells (synapses) where cell-to-cell communication takes place. Connected nerve cells act as the “wiring” in the circuitry of the brain. Synapses are able to change and adapt over time, rewiring brain circuits, which is critical for learning and memory.

SynGAP helps regulate synapse adaptations and promotes proper brain wiring. The protein’s function is particularly important during a critical period of early brain development that affects future cognitive ability.


What is the Impact of a SYNGAP1 Gene Mutation?

A SYNGAP1 gene mutation can cause a variety of symptoms.
Symptoms vary between each individual affected and can range from mild to severe. The most common symptoms include:
  • Learning Disabilities
  • Epilepsy
  • Behavioral Challenges
  • Autism
  • Sensory Processing Disorder




Learn More About SYNGAP1 from
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How does syngap1 affect someone?

Symptoms Related to SYNGAP1
Gene Mutations and Variants

All About SYNGAP1

The SYNGAP1 gene provides instructions for making a protein, called SynGAP, that plays an important role in nerve cells in the brain. SynGAP is found at the junctions between nerve cells (synapses) where cell-to-cell communication takes place. Connected nerve cells act as the "wiring" in the circuitry of the brain. Synapses can change and adapt over time, rewiring brain circuits, which is critical for learning and memory. SynGAP helps regulate synapse adaptations and promotes proper brain wiring. The protein's function is particularly important during a critical period of early brain development that affects future cognitive ability.

 

SYNGAP1 – Non-Syndromic Intellectual Disability (NSID)

SYNGAP1 was initially discovered in 2009 and has become a prominent gene associated with intellectual disability, autism and generalized epilepsy.  Since initially described, an increasing number of children with SYNGAP1-related NSID have been identified, suggesting that it may represent one of the most common causes of ID.  At least 40 mutations in the SYNGAP1 gene have been found to cause SYNGAP1-related intellectual disability. In addition to mild-to-moderate intellectual disability, this condition commonly features other neurological problems, including recurrent seizures (epilepsy)and autism spectrum disorder, which affects communication and social interaction. Gene mutations involved in SYNGAP1-related intellectual disability prevent the production of functional SynGAP protein from one copy of the gene, reducing the protein's activity in cells. Studies show that a reduction of SynGAP activity can have multiple effects in nerve cells, including pushing synapses to develop (mature) too early. The changes triggered by a reduction of SynGAP activity disrupt the synaptic adaptations in the brain that underlie learning and memory, leading to cognitive impairment and other neurological problems characteristic of SYNGAP1-related intellectual disability.

 Intellectual disability (ID) is a common disorder defined by the presence of significant limitations in both cognitive and adaptive behaviors with onset before the age of 18. ID is subdivided into syndromic intellectual disability, in which intellectual deficits and distinguishing morphologic, radiologic or metabolic features are present, and non-syndromic intellectual disability (NSID), in which intellectual deficits appear without these physical abnormalities. Mutations in the SYNGAP1 gene are thought to be a relatively common cause of NSID. NSID patients, including those associated with SYNGAP1 mutation, typically exhibit moderate to severe ID with varying degrees of epilepsy and/or autism spectrum disorders (ASD) and may also have attention deficits, impulsivity, and/or mood disorders. SYNGAP1-related NSID patients with epilepsy usually respond well to medications, yet some are refractory (difficult to control even with multiple drugs). SYNGAP1-related NSID is a sporadic condition that is caused by de novo (spontaneous, non-inherited)mutations. The use of genomic sequencing has dramatically increased the capacity of physicians to identify these gene variants and mutations.

Autism

Approximately 50% of SYNGAP1 patients have been diagnosed with autism.

Characteristics include:

  • Hand flapping
  • Sensory Processing Disorder
  • Self-Injury
  • Obsessive-Compulsive Behavior
  • Poor Social Development

No association has been found between ASD and the severity of ID, or between the location of the mutation on the gene.

Behavior

3/4 of SYNGAP1 patients suffer from severe behavioral problems

Types of Behaviors:

  • Hyper-excitability
  • Aggression
  • Oppositional Behavior
  • Tantrums
  • Self Injury
Eating Difficulties

Oral aversion and oral hypersensitivity are common.

A high percentage of patients suffer from constipation.

A small percentage of patients have G-tubes.

Epilepsy

SYNGAP1 and Epilepsy

  • More than 80% of individuals with SYNGAP1 mutations have generalized epilepsy, with focal seizures occurring only in a minority of cases
  • The age of seizure onset ranges from 3 months to 7 years (most often at 2-3 years)
  • Developmental delays typically precede seizure onset
  • Developmental plateau or regression accompanies seizure onset in many patients, consistent with a diagnosis of DEE.
  • Seizures are quite frequent, ranging from 10-100 per day, but brief, each lasting a few seconds

        Learn more about Epilepsy and SYNGAP1 - Here

Global Developmental Delay

Manifests in the first and second year of life

Motor Delays:

     Sitting unaided average 12 months

  • Walking unaided average 2-3 years

Motor Coordination Issues:

  • Axial and Facial Hypotionia
  • Axtia or Gait instability
  • Strabismus – Lazy Eye

Sensory Processing Disorder: A high percentage of SYNGAP1 patients have a high pain threshold, which interferes with learning. New Research Published in Nature Neuroscience.

Intellectual Disability

Approximately 96% of Patients with pathogenic mutations have intellectual disability ranging from mild to severe.

Language

Severely Impaired with delays in expressive & receptive speech development.

1/3 of individuals over the age of 5 years old remain non-verbal.

Verbal Patients range from single words to brief sentences.

*Milder phenotypes have been observed in patients with mutations 1-4 as compared to more severe phenotypes in exons 8-15.

Sleep Difficulties

60% of patients reported sleep difficulties, both with initiation and maintaining sleep.

Sleep is frequently managed with melatonin, clonidine or trazodone.

SYNGAP1 Information & Research Publication Links

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Production and distribution of this resource are made possible by an educational grant from Greenwich Biosciences.