SYNGAP1 – Autism Spectrum Disorder

SYNGAP1 encodes a RAS-GTPase activating protein critical for excitatory synapse development. Heterozygous de novo mutations in SYNGAP1 lead to a neurodevelopmental disorder characterized by intellectual disability and autism spectrum disorder (ASD) (PMID:19196676). The association has been replicated across multiple cohorts since 2009, establishing SYNGAP1 haploinsufficiency as a key mechanism in ASD pathogenesis.

Genetic evidence supports an autosomal dominant inheritance with de novo occurrence. Over 12 unrelated probands with de novo truncating SYNGAP1 variants have been reported, each presenting intellectual disability and ASD features (PMID:26110312; PMID:23161826). Segregation data are limited due to de novo events, but one instance of parental mosaicism has been documented without additional affected relatives.

The variant spectrum is dominated by loss-of-function alleles (nonsense, frameshift, splice-site), with fewer pathogenic missense mutations. A representative variant is c.348C>A (p.Tyr116Ter), identified de novo in a 15-year-old girl with intellectual disability and ASD (PMID:26110312). No recurrent or founder variants have been described to date.

Functional studies demonstrate that SYNGAP1 haploinsufficiency disrupts downstream Ras-MEK-ERK signaling. In vitro assays show that truncating and missense mutations abolish SYNGAP1-mediated suppression of pERK, while Syngap1+/- mice exhibit enhanced basal synaptic transmission and reduced long-term potentiation, both partially rescued by MEK inhibition (PMID:29940508). These findings confirm loss-of-function as the pathogenic mechanism.

No reports have refuted the SYNGAP1–ASD association. All available data are concordant, with no alternative phenotypes assigned to SYNGAP1 mutations beyond the established neurodevelopmental spectrum.

SYNGAP1 fulfills ClinGen criteria for a definitive gene–disease relationship with ASD. Genetic and experimental concordance over >15 years supports its clinical utility in diagnostic testing and genetic counseling. Key take-home: de novo SYNGAP1 loss-of-function variants reliably predict autism spectrum disorder and intellectual disability, informing precision diagnosis and potential pathway-targeted therapies.

References

• The New England Journal of Medicine • 2009 • Mutations in SYNGAP1 in autosomal nonsyndromic mental retardation PMID:19196676
• Neuropediatrics • 2015 • SYNGAP1 Mutation in Focal and Generalized Epilepsy: A Literature Overview and A Case Report with Special Aspects of the EEG. PMID:26110312
• Human Mutation • 2013 • Mutations in SYNGAP1 cause intellectual disability, autism, and a specific form of epilepsy by inducing haploinsufficiency. PMID:23161826
• Pharmacological Reports: PR • 2018 • Chronic treatment with a MEK inhibitor reverses enhanced excitatory field potentials in Syngap1+/- mice. PMID:29940508

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