Genetics research into autism has made considerable strides in recent years. While it may seem to most lay people that a lot of funding goes into a field that has offered little translational help to those who want and need it, we are nevertheless coming closer to understanding precisely what is this group of very heterogeneous conditions, at which point I’m hopeful more interventions will reveal themselves once we have that foundation of knowledge.
We have learned a lot about rare autism syndromes that have strong genetic bases, which comprise an important minority of the spectrum. Unfortunately, it’s still a mystery how these rare syndromes may or may not relate to the rest of the autism spectrum.
A new article by Rossi et al. (2017) suggests that the genes targeted in rare autism syndromes may in fact be involved in a broader range of the autism spectrum than we’d anticipated.
The team performed exome sequencing on individuals with autism with intellectual disability, epilepsy, or psychiatric conditions, but who didn’t fit any already-recognized syndromes. Using in depth exome sequencing, they found that about 25% of those with autism or autism-like features had a positive genetic result, indicating that they had gene variants that were probable underlying causes of their autism.
Figure 2 from Rossi et al. (2017).
Most interesting of all was that the vast majority of the identified gene variants fell within genes that are already linked with rare autism syndromes. Therefore, even though these cases didn’t exhibit the full syndromes, the same genes were still affected.
The reasons for this are likely due to variations in mutation penetrance. Rare syndromes are often (though not always) the result of large deletion or duplication events, which are highly deleterious to the genes involved and are more likely to result in a consistent constellation of symptoms (i.e., a syndrome).
In contrast, a smaller mutation, such as a point mutation, is typically less deleterious to the functioning of a gene than a large deletion or duplication, and so production of the gene product may be only modestly impaired or the protein prone to misfolding, but it still may be capable of fulfilling some of its duties within the cell. Hence, the phenotype tends to be less severe. (This isn’t always the case, but is a general trend.)
While this study doesn’t address the question as to whether common variants (e.g., single nucleotide polymorphisms or SNPs) in these genes confer measurable autism risk, it does however suggest that a broader portion of the autism spectrum is affected by variants in syndromic genes.
I’m hoping over the next few years we’ll begin to address whether this is also the case for common variants– which are more likely to confer risk to a broader array of the spectrum, in combination with risks from the environment, such as maternal hormone disorders, immune dysfunction, and maternal stress.