We identified protein-truncating de novo mutations in the autosomal gene SYNGAP1 in approximately 3% of our series of patients with nonsyndromic mental retardation. These mutations are probably pathogenic for several reasons. First, they result in the production of proteins that lack domains, such RASGAP and QTRV, that have been shown to be important for the synaptic plasticity and spine morphogenesis that are required for learning and memory.16,19 In addition, each of the resulting premature stop codons could also destabilize the SYNGAP1 messenger RNA (mRNA) transcript through the nonsense-mediated mRNA decay mechanism.21 Second, mice that are heterozygous for null alleles of Syngap1 have impaired synaptic plasticity and learning, which suggests that the disruption of a single SYNGAP1 allele is sufficient to cause cognitive dysfunction in humans.15,16 Third, extensive screening of 475 subjects without nonsyndromic mental retardation, including a subgroup with autism spectrum disorders and another with schizophrenia, did not identify any truncating, splicing, or de novo amino acid–altering variants in SYNGAP1. This finding reinforces the idea that the disruption of this gene is specifically associated with nonsyndromic mental retardation.
