Tuesday, 22 November 2011

CNVs and intellectual disability

A very quick post based on an interesting paper published in PLoS Genetics by Girirajan and colleagues* on our old friends the copy number variations (CNVs).

The paper is open access so no need for me to summarise too much but I will say:

  • Samples from over 1200 individuals were analysed for the frequency of large CNVs in genomic hotspots. Individuals were grouped into those with dyslexia, autism and intellectual disability (ID) (with an asymptomatic control group also included).
  • The appearance of various large CNVs between the groups seemed to suggest that the presence of intellectual disability was the primary correlate. So in the ID group (n=501) the odds ratio of possessing a large CNV was 13.71 with a p-value (significance) going down to about 17 decimal places (highly significant). The autism group (n=350) also showed greater odds of possessing a large CNV (odds ratio = 2.99) although nowhere near as significant as in the ID group (p=0.012). The dyslexia group also relative to controls showed... nothing.
  • Dividing the autism group up into those with (n=97) and without ID (n=253) continued the trend towards a relationship between large CNVs and cases with ID, although this was not found to be significantly different between the groups (p=0.102).
  • When looking at rare CNVs (less than 50% overlap of CNV length with those found in controls) there was more of an association with autism (10% of participants carrying 36 rare CNVs, odds ratio=6) and also continuing the relationship with ID (16% of participants carrying 77 rare CNVs, odds ratio=10). Dyslexia with regards to rare CNVs again showed nothing compared to asymptomatic controls. Nearly half of the rare CNVs reported in autism or ID groups seemed to be de novo (so not passed from parents).

There is a lot more data in this paper on what was found CNV-wise and in which group. Interesting was the degree of overlap between the results from the conditions looked at; so for example, CNVs in the region coding for the AUTS2 variant being found in two cases of dyslexia. Interesting also that the numbers of cases of autism carrying CNVs is about the same as picked up in other studies (10-11%).

I was struck by the relationship suggested in this study between large CNVs and intellectual disability. Very recently I posted an entry regarding CNVs and ADHD which seemed to arrive at a similar conclusion on the involvement of intellectual disability and CNVs. This combined with the current study and the fact that dyslexia is not usually viewed as an intellectual disability (as opposed to a learning or reading disability) adds further weight to the relationship.

The bottom line I suppose from this study is that autism is a very complicated condition, and the whole really is greater than the sum of its parts in terms of the various comorbidity which can and do appear alongside. CNVs may represent one strand of that complexity but with 90% of cases from this study showing no rare CNVs, perhaps we should be looking elsewhere, perhaps to epigentics and environment for some of the answers?

* Girirajan S. et al. Relative burden of large CNVs on a range of neurodevelopmental phenotypes. PLoS Genetics. November 2011.