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The male to female ratio in autism spectrum disorder is around 4:1. However it seems ASD is not a simple X-linked disorder.

Then how is it possible males are more susceptible than females, if the causal genes are located in autosomes?

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Could you maybe add some background, e.g. references on the incidence of autism spectrum disorders? – fileunderwater Jun 13 '13 at 11:12
Sure, I will do this later when I come to school – tky Jun 14 '13 at 0:47
up vote 5 down vote accepted

As the father of two sons with diagnoses of ASD, I think that it is best to think in terms of an extended spectrum which encompasses 'normal' people. We are all somewhere on this spectrum, but there is a threshold zone around where we cross from "normal" to "diagnosable as ASD". Now, if the distribution of spectral position for males is displaced towards the ASD end of the spectrum relative to females (because of some aspect underlying "normal' maleness, such as testosterone levels) then any genetic variation which pushes someone towards the ASD end of the spectrum by some fixed amount will tend to push more males over the threshold than females.

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That is an interesting idea. Do you know if there's a database of scores on an ASD questionnaire, for the general population so that we could verify it? Simon Baron-Cohen's tests come to mind, but I'm not sure if they've looked at the distribution of scores. – dd3 Jun 12 '13 at 23:37
Dear Alan, thanks for sharing the point. I hope the genetics study in the future can explain the mystery. – tky Jun 13 '13 at 15:05
Nice thinking @alan-boyd, I wonder would it be nice to see a study correlating "manliness traits" with ASD test scores? – rg255 Jun 24 '13 at 19:06

Males are more likely to develop ASD, but affected females tend to be more severely impaired. Why this occurs is an area of active research.

However, to address your question, there is a study suggesting that mutations on the X-chromosome account for about 1% of ASD and intellectual disability cases. This clearly doesn't explain everything, but it's a start. It might suggest that there are other X-linked loci involved. IIRC, ASD is one of those disorders that can be caused by many different combinations of (relatively rare) mutations, so it's hard to identify the genetic causes by GWAS.

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hi, thanks a lot for the explanation. Another question came to my mind is that the one copy of X chromosome will be silenced (please correct me if I am wrong),so does the X chromosome which carry mutation always be deactivated? – tky Jun 13 '13 at 15:07

I'm not expert on the topic, but whenever males more predominately have a condition than females, it might point to a sex-linked (recessive) trait. Males have one X chromosome, while females have two. This means that a male only needs one copy of a gene to have a condition (inherited from their mother), while females need two X chromosomes to be inherited to have the condition (mother and father).

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