Expression of autism spectrum and schizophrenia in patients with a 22q11.2 deletion
Introduction
In recent years, increasing numbers of structural genomic variants, in particular rare, recurrent copy number variants (CNVs), have been identified as risk factors of large effect for neuropsychiatric disorders (Sebat et al., 2007, International Schizophrenia Consortium, 2008, Stefansson et al., 2008, Walsh et al., 2008, Bassett et al., 2010). Initial studies suggested that certain CNVs appeared to be associated with specific disorders. Cumulative reports, however, indicate that the same variant may be a risk factor for several neuropsychiatric and developmental disorders (Girirajan and Eichler, 2010). Examples include the 15q13.3 deletion associated with schizophrenia (Stefansson et al., 2008), autism (Pagnamenta et al., 2009), intellectual disability (Sharp et al., 2008) and generalized epilepsy (Helbig et al., 2009) and 16p11.2 deletions and duplications with schizophrenia (McCarthy et al., 2009), autism (Weiss et al., 2008), and intellectual disability (Girirajan et al., 2010). When one genetic variant can lead to two or more distinct, unrelated or seemingly unrelated, phenotypes, the variant can be considered pleiotropic. Pleiotropy is a common biological phenomenon in which one genetic variant has the potential to result in two or more distinct phenotypic manifestations.
Can we better understand the pleiotropy of genetic variants, in particular in CNVs? The first question to address is whether the observed expression truly represents pleiotropy. For example, the most common recurrent CNV, the 22q11.2 deletions associated with 22q11.2 deletion syndrome (22q11.2DS), are associated with congenital cardiac defects (Cohen et al., 1999) and schizophrenia (Murphy et al., 1999). These two phenotypes occur independently, i.e. in 22q11.2DS the presence or absence of cardiac defects is not associated with an altered risk for schizophrenia (Bassett and Chow, 2008), consistent with true pleiotropy. Pseudopleiotropy, by contrast, would refer to phenotypes that are observed as discrete manifestations while in reality, they are expressions of the same pathological process, for instance at different developmental stages. This distinction may be particularly relevant with regard to the association of both autism spectrum disorders (ASDs) and schizophrenia with several pathogenic CNVs. In this regard, it has been suggested that the high prevalence of autistic behaviors in children with 22q11.2 deletions should not be viewed as autism spectrum disorders (ASDs), but rather as prodromal symptoms preceding the onset of schizophrenia (Vorstman et al., 2006, Eliez, 2007, Crespi and Badcock, 2008, Karayiorgou et al., 2010). If a marker such as childhood autistic behaviors could be shown to predict the development of schizophrenia, a later onset condition occurring in approximately 20–25% of individuals with 22q11.2DS, this would be important in guiding anticipatory clinical care for this vulnerable group. Alternatively, if schizophrenia and autistic features appear as independent expressions in 22q11.2DS, this could be exploited in studies of the underlying brain changes and pathogenesis.
Using an adult cohort with 22q11.2DS where reports of the presence of childhood ASD symptoms were available, we tested the hypothesis that ASD during childhood would be associated with higher rates of psychotic disorders in adulthood. We proposed the following possible scenarios:
- A.
In 22q11.2DS, the ASD phenotype in childhood is associated with schizophrenia in adulthood because either
- 1)
the ASD features observed in children with 22q11.2DS are in fact prodromal to the onset of schizophrenia (consistent with developmental pseudopleiotropy), or
- 2)
the ASD features in 22q11.2DS during childhood are related to expression of autism and the close association with schizophrenia is the result of shared pathogenesis between these two conditions; or
- 1)
- B.
The ASD phenotype in 22q11.2DS is not associated with the expression of schizophrenia in 22q11.2DS, consistent with true pleiotropy, and supporting the null hypothesis.
Section snippets
Participants and procedure
Parents of adults with 22q11.2DS followed at the Clinical Genetics Research Program, Centre for Addiction and Mental Health at the University of Toronto, were asked to participate in this study. In all subjects with 22q11.2DS the hemizygous 22q11.2 deletion was clinically confirmed by fluorescence in situ hybridization (FISH) using a standard probe (e.g., TUPLE1) (Bassett et al., 2008). As expected, in the majority of cases (> 90%) the 22q11.2 deletion was a de novo event (Bassett et al., 2008).
Results
The mean “reference age” used by the parents for the two autism scales was similar in the 22q11.2DS-SZ group and the 22q11.2DS-Co; 5.9 ± 2.0 and 6.4 ± 2.0 years respectively, p = 0.217 (Mann–Whitney–Wilcoxon). In comparison to the 22q11.2DS-Co group, the subgroup with schizophrenia was older (36.6 (95% CI 33.1 to 40.2) vs. 28.5 (26.2 to 31.1) years, p = 0.001 (Mann–Whitney–Wilcoxon)) and on average had lower IQ (69.7 (66.5–73.2) vs. 75.7 (72.4–79.2), t = − 2.40, p = 0.02). There were no significant sex
Discussion
The results of this study support the possibility that ASD and schizophrenia should be considered as distinct, pleiotropic neuropsychiatric consequences of a 22q11.2 deletion. Although we found high levels of probable ASD, autistic or autistic-like symptoms during childhood, in line with previous findings of elevated prevalence of ASDs in children with 22q11.2DS (Niklasson et al., 2001, Niklasson et al., 2009, Antshel et al., 2007, Vorstman et al., 2006), the results did not support the
Conclusion
The current study provides evidence that in 22q11.2DS patients, ASD or autistic symptoms during childhood are not correlated with schizophrenia in adulthood. Therefore, ASDs and/or autistic symptoms cannot be considered as indicating premorbid symptoms of schizophrenia and would therefore not be useful as markers for increased vulnerability for schizophrenia in 22q11.2DS. Although the results may or may not apply to the variability of neuropsychiatric disorders observed in other pathogenic
Role of funding source
This work was supported by grants from the Canadian Institutes of Health Research (MOP-79518, MOP-97800) and W. Garfield Weston Foundation (ASB, EWC). Dr. Bassett holds the Canada Research Chair in Schizophrenia Genetics and Genomic Disorders. J.A.S. Vorstman M.D., Ph.D. was supported by a 2006 NARSAD Young Investigator Award, funded by Stephen and Constance Lieber.
Contributors
Authors JV and AB took part in designing the study. Authors JV, AB, KT and EC collected the data. Author EB carried out the statistical analyses. Author JV wrote the first draft of the manuscript. Author AB contributed significantly to the writing of subsequent versions. All authors contributed to and have approved of the manuscript.
Conflict of interest
All authors declare that they have no conflicts of interest.
Acknowledgements
None.
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2020, Biological PsychiatryCitation Excerpt :However, the mechanisms by which reciprocal deletions and duplications at the same locus can have divergent effects on intellectual dysfunction and psychosis-related traits (17,18,32,33) but converge on similar impairments for specific cognitive domains and social cognition remain unknown. Notably, ASD diagnosis does not appear to increase risk of subsequent development of SCZ in 22q11.2 deletion carriers, suggesting pleiotropic effects of 22q11.2 gene dosage, at least with regard to these neurobehavioral outcomes (66,67). Animal models of 22q11.2 CNVs involving over- or underexpression of specific genes within the homologous 22q11.2 locus offer crucial insight into potential mechanisms that underlie brain and behavioral dysfunction in human CNV carriers.