SYNGAP1-related intellectual disability

The first signs of SYNGAP1-related encephalopathy are typically gross motor delays in infancy followed by developmental delays, seizure onset and language impairment.[2] Penetrance is 100%. Mild to severe intellectual or developmental disability is present in the majority of patients.[3] Epilepsy is present in almost all cases, with approximately 94-98% of patients affected by seizures.[4] Truncal hypotonia and clumsy gait are typical. Behavioral and sleep problems are also common.[5] Approximately 50% of patients receive a diagnosis of autism spectrum disorder.[4] Some patients have significant feeding issues.[3]

SYNGAP1 encephalopathy is an autosomal dominant genetic disorder caused by haploinsufficiency of the SynGAP protein, usually due to the presence of a heterozygous protein-truncating loss-of-function variation on the SYNGAP1 gene. Missense variations, which may result in either a loss or a change-of-function can also result in the disorder. These pathogenic variations disrupt early cognitive development, particularly in the hippocampus and cortex.[5]

The majority of mutations are considered de novo, however cases of inheritance from both somatic mosaic and germ-line mosaic parents have been reported.[6]

Diagnosis is based on genetic testing, with the recommended testing approach being Chromosomal Microarray Analysis followed by an Intellectual Disability multigene panel or Whole Exome Sequencing. A diagnosis is established following the identification of a heterozygous pathogenic (or likely pathogenic) point mutation of the SYNGAP1 gene (present in approximately 89% of patients), a micro deletion of chromosome 6 incorporating SYNGAP1 (approximately 11% of patients), or a balanced translocation disrupting SYNGAP1.[6][3]

EEG monitoring frequently shows generalized epilepsy, predominantly in the occipital regions.[6] MRI is usually normal.[3]

There is currently no cure or causative treatment. Epilepsy may be controlled by the use of one or more anti-epileptic drugs, however approximately half of patients have seizures that are pharmacoresistant.[5] Patients with significant feeding issues may require the use of a gastrostomy tube. Communication may be supported with the use of an Augmentative and Alternative Communication device. Patients with significant mobility or gait issues may require the use of wheelchairs, adaptive strollers or Ankle Foot Orthoses.

Supportive treatments can include:[9]

• Applied Behavior Analysis
• Feeding Therapy
• Occupational Therapy
• Physical Therapy
• Speech and Language Therapy

Despite the common mechanism of haploinsufficiency, there is distinct phenotypic variability amongst patients. Although one third of patients are non-verbal, others can communicate with single words, while others can speak conversationally using 4-5 word sentences.[3]

SYNGAP1 encephalopathy is estimated to comprise approximately 0.7- 1% of all cases of intellectual disability[10][11] with over one million people expected to be affected worldwide.[12][13]

Although the SynGAP protein was first identified in 1998,[14] SYNGAP1 mutations were not found to be responsible for cases of intellectual disability until 2009.[15]

The use of antisense oligonucleotides to upregulate the expression of SynGAP protein is currently being researched.[16] The use of statins to address the downstream impacts of loss of SynGAP function on the Ras signaling pathway is also being studied.[17]

• Syngap Global Network
• Syngap Research Fund
• Bridge the Gap – SYNGAP Education and Research Foundation