This study revealed an association with autistic features in males with an extra sex chromosome. Around 20% of XYY males and 11% of XXY males had received a diagnosis of ASD, which is a 10–20-fold increase over even the most liberal prevalence estimate for autism in the general population.15
Furthermore, among those who did not have an ASD diagnosis, there was evidence of milder communicative difficulties similar to those seen in autism. It is noteworthy that a significant increase in ASD was seen in males from Group I, who were identified prenatally, before there was any concern about the child’s development. Although girls with XXX karyotype also had a high rate of educational difficulties and frequently had received speech and language therapy, none had an ASD diagnosis, and the CCC-2 profile suggested few had major communicative problems.
Despite these associations with impairment, when attention is focused on Group I, 14% of XYY boys, 37% of XXY boys and just over half the XXX girls had not been noted as requiring support services nor received any educationally relevant diagnosis. These results confirm previous reports from studies of samples identified by newborn screening, in revealing an increased prevalence of educational difficulties and speech-language problems in children with SCTs, but with many nevertheless coping in mainstream schools, and some children performing within the normal range.3
ASD, however, was not mentioned in those earlier studies, where the emphasis was more on language and literacy problems, as well as a general reduction in IQ. A possible explanation for this mismatch is a change in diagnostic practices which means that children who in previous years would have been identified as cases of language disorder may now be diagnosed with ASD.16
The association between autistic features and SCTs is of both clinical and theoretical significance. Parents whose child is diagnosed with an SCT often feel they do not get adequate information about the implications of the diagnosis. It is important not to give an unduly negative prognosis and to keep in mind that not all children with SCTs will have educational difficulties. Nevertheless, if a child does experience problems, parents need to be directed to the most appropriate sources of help, and this will be facilitated if clinicians are alerted to the fact that ASD may be implicated.
As research on genetics of neurodevelopmental disorders proceeds, it has become increasingly clear that the phenotypes of autism and SLI can be a common result of perturbation of a wide range of different mechanisms.17
Although our data indicate an increase in the relative risk of ASD and language difficulties with SCTs, most children with communication disorders have a normal karyotype,18 19
and these trisomies cannot provide any general explanation for these neurodevelopmental disorders. Nevertheless these findings point to a possible role for genes on both the X-chromosome and Y-chromosome, and the neuroligin genes (NLGN) are attractive candidates as they code for cell adhesion molecules involved in the formation of functional synapses, and have been implicated in autism.20 27
There are two NLGN genes on the X-chromosome: NLGN3 and NLGN4X, the latter located on Xp22 where the majority of genes are expressed from both the active and the inactive X.25
There are very few genes on the Y-chromosome, but NLGN4Y is located on the male-specific region of the Y and is highly homologous with NLGN4X.28
It is expressed in brain, and all other tested tissues.
Our data suggest a triple dose of such genes is a strong risk factor for language difficulties, with additional social impairments being found when it occurs in a male, leading to autistic features. This account is, however, complicated by evidence that in Turner syndrome, where there is 45, X karyotype, the prevalence of autism is around 3%—lower than that seen in males with SCTs, but substantially higher than in the general population of females.29
Language, however, is not usually impaired in 45, X females. We therefore hypothesise that risk of autism is increased when there is either deficit or over-expression of X-linked and Y-linked NLGNs; this kind of mechanism, where autism is associated with too much or too little gene product, has been demonstrated for CNVs on 16p11.2.30
Thus, aberrant gene dosage of NLGNs may provide a common mechanism underpinning the excess of ASD in XYY and XXY males, and in 45, X females.
An alternative hypothesis would maintain that the social impairments seen in 45, X, 47, XXY and 47, XYY karyotypes are less similar than they seem on the surface, with social anxiety being at the root of the difficulties of some children and lack of empathy characterising others.31
More detailed investigations of the phenotype are now needed to clarify these issues.