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Clinical research: Extra X increases risk of autism

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Jessica Wright
7 January 2014

Risk group: Doctors should note that boys with Klinefelter syndrome are also at risk of developing autism.

Men who have an extra X chromosome have an elevated risk of developing autism, schizophrenia or bipolar disorder, according to a study published in the January issue of the Journal of Psychiatric Research1.

The results provide further support for a connection between autism and the X chromosome. Several X chromosome genes — including the genes that lead to fragile X syndrome and Rett syndrome, along with NLGN3 and NLGN4 — are linked to autism. Mutations in X chromosome genes may explain the higher prevalence of autism in males than in females.

About 1 in 670 men have Klinefelter syndrome, which is caused by having two X chromosomes and one Y. Men with the disorder have symptoms consistent with having low levels of testosterone, such as small testes and enlarged breasts. Studies also suggest that they have an increased risk of developing neurological disorders such as schizophrenia2, 3.

In the new study, researchers combed the Swedish National Patient Register to find 860 men with Klinefelter syndrome living in Sweden. They matched each of these men with 100 men from the general population born in the same year and country.

Men with Klinefelter syndrome are four times more likely to be diagnosed with schizophrenia or bipolar disorder and six times more likely to have a diagnosis of autism than are controls, the study found.

It is possible that people with both Klinefelter syndrome and a neurological syndrome are more likely than those with either syndrome alone to seek medical attention, the researchers note. Still, the results suggest that an extra copy of genes on the X chromosome increases the risk of neurological disorders. 

News and Opinion articles on SFARI.org are editorially independent of the Simons Foundation.


1: Cederlöf M. et al. J. Psychatri. Res. 48, 128-130 (2014) PubMed

2: Bruining H. et al. Pediatrics 123, e865-870 (2009) PubMed

3: van Rijn S. et al. Br. J. Psychiatry 189, 459-460 (2006) PubMed


Name: RAJensen
12 January 2014 - 3:34PM

Klinefelter Syndome is not inherited. It is alway caused by a reproductive error, an extra X chromosome producing the XXY genotype. Half the cases are caused by an XX sperm mutation and half are produced by an XX egg mutation.

McCauliife et al found that 'Our findings suggest that exposure to p,p´-DDE may be associated with increased rates of XX, XY, and total sex-chromosome disomy, whereas exposure to PCBs may be associated with increased rates of YY, XY, and total sex-chromosome disomy. In addition, we observed an inverse association between increased exposure to PCBs and XX disomy;.


Name: Virginia Cover
25 May 2014 - 3:12PM

Those of with children with extra x and y chromosomes have known for a number of years that these children are much more likely to be diagnosed with ASD than the general population of kids. It has been quantified fairly recently. Boys with XXY (Klinefelter syndrome) have an 11-20% of also meeting the criteria for autism on ADOS. In the Netherlands, 25% of adults with XXY meet the criteria for Asperger syndrome. Interestingly, 30% of boys with XYY, an extra Y chromosome, have ASD. Being a girl seems to be protective; less than 9% of girls with Trisomy X, (47,XXX), have ASD. Studying this population of children and adults with supernumerary X and Y chromosome can provide important clues to one of the causes of autism. For more information on sex chromosome aneuploidy, visit www.axysinfo.org, the website of AXYS association for x and Y variations.

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