De novo autosomal dominant mutation in SYNGAP1.

03Original abstract

Initial genetic studies of intellectual disability (ID, formerly known as mental retardation) focused on syndromal intellectual disability, in which there was involvement outside of the central nervous system ranging from dysmorphology to cardiovascular abnormalities. However, a recent development in intellectual disability research has been the productive study of the genetics of individuals with nonsyndromal intellectual disability (NSID). In ASD, the possibilities can be nonsyndromal ASD with or without ID or syndromal ASD with or without ID. In thinking beyond ASD, one may study NSID with or without ASD, which is what the authors of the paper under review did. They selected 30 children with NSID with ASD and 30 children with NSID without ASD. There were 20 males and 10 females in the NSID with ASD group and 15 male and 15 females in the NSID without ASD group. The investigators also studied 380 control subjects. The authors had previously identified three subjects with de novo mutations in the gene, SYNGAP1 [Hamdan et al., 2009]. SYNGAP1 is a brain-specific protein that interacts with key components of the proteins involved in experience-dependent changes in glutamate synapses involved in learning. In this study, they found de novo (not found in the parents of the children with NSID) mutations in SYNGAP1 in one of the 30 children with NSID and autism and two of the 30 with NSID without autism. In addition to the supporting evidence that a de novo event provides, the effect of each mutation was to truncate, or cut off, the end of the protein involved in interaction with other proteins related to the regulation of synaptic strength in response to experience. In two cases, there was a deletion that interrupted the way the protein was read so that it stopped prematurely and in another case, there was a splicing change that led to skipping of an exon and then led the reading frame to be disrupted. Proteins are coded for by genes with three nucleotides coding for one amino acid—therefore, if there is an insertion or deletion in the coding part of the gene that is not a multiple of three nucleotides, the way that the letters are read 3 at a time is not as intended. Therefore, not only are different amino acids added to the protein, but a three-letter code for “stop” is more likely to occur prematurely and lead to a shorter protein. In a previously reviewed paper for this series in Volume 3, issue 4, Pinto et al. [2010] reported a subject with ASD who had a deletion that included SYNGAP1 and several other genes. The paper being reviewed at this time is more specific to a single gene rather than the set of genes found in the de novo copy number variant (CNV) found in the earlier paper. This provides converging evidence for the involvement of SYNGAP1 in ASD pathophysiology. This is similar to convergence of deletions including SHANK3 and amino acid variants in SHANK3 in ASD. One interesting concept in the de novo mutations identified here is that they are considered to be autosomal dominant. One more typically thinks of an autosomal dominant mode of inheritance in which each generation is affected and 50% of offspring are affected. However, with severe mutations in which only one chromosome has a mutation with severe effect, the mutation is autosomal dominant but less likely to be transmitted once it occurs. This is one reason that more weight is given to the interpretation of the causality of a de novo mutation. Therefore, the de novo status of these mutations was important to validate. One important step followed by these investigators was to confirm relationships by markers unrelated to SYNGAP1 that confirmed that there had not been a mistake in the assignment of parents to each child, i.e. they excluded nonmaternity or nonpaternity. This study also prepares the reader for the onslaught of findings emerging as sequencing capacity moves to much higher throughput than sequencing each exon individually. Sequencing of the vast majority of exons throughout the genome is being conducted in more than ten times the number of ASD subjects in the study under review. One may expect identification of further genetic variants contributing to autism pathophysiology and further genetic variants that will be more difficult to interpret than the de novo truncating mutations in this study. Most importantly, identification of mutations in genes such as SYNGAP1 provides one more piece to help understand autism pathophysiology.

Autism research : official journal of the International Society for Autism Research, 2011 · doi:10.1002/aur.198