Why is autism diagnosed more often in boys than girls? True, there is some evidence to suggest that the diagnostic criteria themselves were based primarily on males and therefore better reflect autism as it occurs in the male sex. There is also genetic evidence that indicates females who are lower functioning are that much more likely to carry loss-of-function (LOF) mutations than their male counterparts. But is there another piece to add to this ever-growing puzzle of sex differences in the autism spectrum?
In a multisite collaborative effort, a group of scientists has found exactly that. The team looked at single nucleotide polymorphisms (SNP) (common gene variations) associated with autism, investigating a variety of possibilities how sex differences may arise:
- Do females require a greater number of common polymorphisms to occur together to reach cutoff for autism?
- Is the heterogeneity due to genes on the X chromosome?
- Is there a gene x sex interaction on other chromosomes?
- Are risk genes specific targets for steroid hormones like estrogen and testosterone? Are they expressed differently in male vs. female brains?
- Are the polymorphisms that differentially associate with the sexes also somehow related to other secondary sex features like height, hip size, etc.?
One of the results I personally found surprising was that, when it came to common gene variants, females didn’t appear to have any heavier genetic load than the males. There were, however, definitely sex-associated SNPs that occurred on the X chromosome.
There also wasn’t any evidence that risk genes were especially targeted by hormones and didn’t vary much in expression patterns in the brain across the sexes.
What the researchers did find, however, was that autism SNPs tended to be associated with secondary sex traits, such as height, body mass index (BMI), hip size, and waist measurements. And although there was no significant signal on its own, hormone-targeted SNPs significantly overlapped SNPs associated with secondary sex features.
This suggests that, evolutionarily, as the human form has changed so has risk for autism. And it also suggests that hormones have played roles in the different expression patterns of risk genes across the sexes. As such, female hormones may be a protective factor against greater autism severity through differentially affecting specific risks genes that, in turn, also play roles in determining physical characteristics like height and body mass.
I then wonder why autism spectrum conditions occurr more frequently in 47,XXY than in 46,XY. It appears like as if the secondary X chromosome is less silenced than in women. Still, there are differences as the “milder” forms of autism (Asperger, PDD-NOS) occurr more often in 47,XXY. Kind of protective effect? The phenotype of XXY is especially visible in these secondary (female) sex traits, like broader hips, gynecomastia, pubic hair and gentle hands.
Hard to say. As you mention, the milder forms are typically seen with Klinefelter’s. The feminized traits are also not typically as extreme as seen in typical females, suggesting hormone levels are not identical. So there could be some protection afforded, but also risk due to duplication of X genes and presence of more male hormones. So it’s probably rather complicated.