What is 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 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 on 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.

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.

3/4 of SYNGAP1 patients suffer from severe behavioral problems.

Types of Behaviors:

-Hyper-Excitability
-Aggression
-Oppositional Behavior
-Tantrums
-Self Injury

Oral aversion and oral hypersensitivity are common. A high percentage of patients suffer from constipation. A small percentage of patients have G-tubes.

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

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 Hypotonia
Ataxia 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.

Approximately 96% of patients with pathogenic mutations have intellectual disabilities ranging from mild to severe.

Language
Severely impaired with delays in expressive and receptive speech development.

1/3 of individuals over the age of 5 years old remain nonverbal.

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.