Clinically detectable copy number variations in a Canadian catchment population of schizophrenia

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Abstract

Copy number variation (CNV) is a highly topical area of research in schizophrenia, but the clinical relevance is uncertain and the translation to clinical practice is under-studied. There is a paucity of research involving truly community-based samples of schizophrenia and widely available laboratory techniques. Our objective was to determine the prevalence of clinically detectable CNVs in a community sample of schizophrenia, while mimicking typical clinical practice conditions. We used a brief clinical screening protocol for developmental features in adults with schizophrenia for identifying individuals with 22q11.2 deletions and karyotypically detectable chromosomal anomalies in 204 consecutive patients with schizophrenia from a single Canadian catchment area. Twenty-seven (13.2%) subjects met clinical criteria for a possible syndrome, and 26 of these individuals received clinical genetic testing. Five of these, representing 2.5% of the total sample (95% CI: 0.3%–4.6%), including two of ten patients with mental retardation, had clinically detectable anomalies: two 22q11.2 deletions (1.0%), one 47, XYY, and two other novel CNVs – an 8p23.3-p23.1 deletion and a de novo 19p13.3-p13.2 duplication. The results support the utility of screening and genetic testing to identify genetic syndromes in adults with schizophrenia in clinical practice. Identifying large, rare CNVs (particularly 22q11.2 deletions) can lead to significant changes in management, follow-up, and genetic counselling that are helpful to the patient, family, and clinicians.

Introduction

For developmental conditions like autism and mental retardation new genetic technologies such as microarrays have extended longstanding associations with cytogenetic abnormalities to include submicroscopic copy number variations (CNVs) (Edelmann and Hirschhorn, 2009, Liang et al., 2008, Weiss, 2009). Schizophrenia is also considered to have neurodevelopmental pathogenesis but has less evidence for associated cytogenetic anomalies than developmental disorders (Bassett et al., 2001a). Research studies using high-resolution techniques have recently focussed attention on CNVs that may be associated with schizophrenia (Bassett et al., in press, Walsh et al., 2008: Xu et al., 2008), including emerging microdeletion (e.g., 1q21.1, 15q13.3) and microduplication (e.g., 1q21.1, 16p11.2) syndromes (Bassett et al., in press). However, 22q11.2 Deletion Syndrome (22q11DS) (OMIM #188400/#192430) currently represents the only genetic subtype of schizophrenia that is both clinically recognizable and associated with a recurrent CNV for which genetic testing is broadly available (Bassett and Chow, 2008). Typical developmental features involve multiple systems, and include dysmorphic facies, learning difficulties, hypernasality often associated with velopharyngeal insufficiency, and cardiac and other birth defects (Bassett and Chow, 1999). Prevalence of major psychotic disorders in 22q11DS is 20–25% (Fung et al., in press). The estimated general population prevalence of 22q11DS is 0.025% (Goodship et al., 1998) while reported prevalences in schizophrenia range from 0 to 2.0%, likely relating to ascertainment strategies such as not studying a truly representative community sample (Bassett and Chow, 2008).

Mimicking typical clinical practice conditions, we previously showed the value of brief clinical screening for developmental features in adults with congenital cardiac disease for identifying individuals with 22q11.2 deletions and karyotypically detectable chromosomal anomalies (Fung et al., 2008). Using the same protocol to identify those with possible genetic syndromes (Fung et al., 2008), we investigated 204 consecutive patients with schizophrenia from a single Canadian catchment area.

Section snippets

Methods

Unrelated patients aged 18–70 years meeting DSM-IV criteria for chronic schizophrenia or schizoaffective disorder with onset age 13 years or older were sequentially recruited from the only community mental health clinic in a catchment area of 150,000 people in New Brunswick, Canada. The study was approved by local and university institutional review boards.

We approached 234 consecutive patients meeting inclusion criteria. Thirty were too ill to provide informed consent, refused participation,

Results

Table 1 shows the demographic and clinical features of the 204 participants. Mean age at onset was significantly younger for males (24.0 years, SD 6.9) than females (27.7 years, SD 10.7; t = 2.9, df = 202, p = 0.004). Twenty-seven (13.2%) subjects met Syndromal criteria. Mean educational level was significantly lower, age non-significantly younger and seizures non-significantly more prevalent in this group (Table 1).

Of 26 Syndromal subjects tested (one died before testing), five (19.2%) had a

Discussion

The results of this study support the value of clinical screening for features of genetic syndromes in schizophrenia. The high prevalence of anomalies discovered in the Syndromal subgroup (19.2%) indicates that our clinical protocol successfully identified individuals for standard genetic testing who had an elevated a priori probability of an anomaly (Fung et al., 2008). Although developmentally-based, the protocol did not rely on comorbid mental retardation. There are several other emerging

Role of funding source

This research was supported by a Canadian Institutes of Health Research grant (MOP-79518), and a Canada Research Chair in Schizophrenia Genetics (Author Bassett). These funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.

Contributors

Author Bassett designed the study. Authors Bassett and Chow contributed to writing the original protocol. Authors Costain, Forsythe, Kapadia, and Russell assisted with data collection and clinical screening. Author Carter supervised the molecular cytogenetic analyses. Author Pierce assisted with the statistical analysis. Authors Bassett, Costain, Fung, Pierce, and Russell wrote the manuscript drafts. All authors contributed to and have approved the final manuscript.

Conflict of interest statement

None of the authors have financial interests that might present a conflict of interest.

Acknowledgements

The authors thank the patients and their families for their participation, colleagues for referring patients, research assistants, staff at the Saint John Community Mental Health Services, fellows and students who assisted in the collection and analysis of data for the study, and Gladys Wong for helping to prepare the manuscript.

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