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Why autism is rarer in girls: new genetic theory

Analysis of a study published in a science journal   |   By Dr Philippa Brice   |   Published 15 June 2011
Study: Rare De Novo and Transmitted Copy-Number Variation in Autistic Spectrum Disorders Neuron
By: Levy D. et al. (17 authors total)
In: Neuron
Link: http://www.ncbi.nlm.nih.gov/pubmed/21658582
What this study set out to do:

Examine the genetic contribution to autistic spectrum disorders (ASDs) by looking at genomic copy-number variants (CNVs) in families. 

How they went about it:

Around 1000 families with a single affected child and at least one unaffected sibling were recruited, and DNA analysed using array-based comparative genomic hybridization (CGH) to search for de novo CNVs , (present in one or more children, but not parents). This genome-wide study was able to detect smaller CNVs than a similar earlier study (see previous news). 

Outcome:

New CNVs were identified in 7.9% of children with ASD, compared with 2% of unaffected siblings. Affected females showed a higher frequency of new mutations (11.7%) than affected males (7.4%), as well as much higher numbers (a median of 15.5 new mutations compared with just 2.0 in males). Most new CNVs were unique, but recurring CNVs were identified at positions on chromosomes 7, 15 and 16. 

Conclusion:

New CNVs contribute to the development of ASDs, but girls are more resistant to disease than boys, possibly because faster early female brain development has a protective effect.  A second paper [Sanders SJ et al. (2011) Neuron 70(5):863-85] uses alternative arrayCGH platforms to analyse a larger group including the same families, with broadly consistent findings. A third paper [Gilman SR et al. (2011) Neuron 70(5):898-907] explores a network of 70 genes thought to be involved in ASD (around 40% perturbed by the mutations observed in this study), and concludes that it is a disease of abnormal synaptic and neuronal connectivity, as previously suggested 

Our view:

This trio of papers provide a fascinating insight into the complex genetics underlying ASDs. Although the genetic theory of the basis of autism presented may not be wholly correct, the potential mechanism for the observed lower frequency of disease in girls is an attractive one. The authors also correctly note that the underlying genetic diversity of ASD may mean that potential treatments could be effective only in very specific sub-groups of patients, and call for exome sequencing of at least 3000 families to identify conclusively the genetic causes of ASDs’

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