Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome |
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Authors: | Rosanna Weksberg Jeremy A Squire Laura Moldovan Jane Bayani Stephen Meyn Eva Chow Anne S Bassett |
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Institution: | (1) Division of Clinical and Metabolic Genetics, Department of Paediatrics, The Hospital for Sick Children, 555 University Ave., M5G 1X8 Toronto, ON, Canada;(2) Department of Molecular and Medical Genetics, University of Toronto, Toronto, ON, Canada;(3) The Research Institute, The Hospital for Sick Children, Toronto, ON, Canada;(4) Institute of Medical Science, University of Toronto, Toronto, ON, Canada;(5) Ontario Cancer Institute and Department of Laboratory Medicine, Pathology and Medical Biophysics, University of Toronto, Toronto, ON, Canada;(6) Department of Psychiatry, University of Toronto, Toronto, ON, Canada;(7) Clinical Genetics Research Program, Centre for Addiction and Mental Health, Toronto, ON, Canada |
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Abstract: | 22q11 Deletion syndrome (22q11DS) is a common microdeletion syndrome with variable expression, including congenital and later
onset conditions such as schizophrenia. Most studies indicate that expression does not appear to be related to length of the
deletion but there is limited information on the endpoints of even the common deletion breakpoint regions in adults. We used
a real-time quantitative PCR (qPCR) approach to fine map 22q11.2 deletions in 44 adults with 22q11DS, 22 with schizophrenia
(SZ; 12 M, 10 F; mean age 35.7 SD 8.0 years) and 22 with no history of psychosis (NP; 8 M, 14 F; mean age 27.1 SD 8.6 years).
QPCR data were consistent with clinical FISH results using the TUPLE1 or N25 probes. Two subjects (one SZ, one NP) negative
for clinical FISH had atypical 22q11.2 deletions confirmed by FISH using the RP11-138C22 probe. Most (n = 34; 18 SZ, 16 NP) subjects shared a common 3 Mb hemizygous 22q11.2 deletion. However, eight subjects showed breakpoint
variability: a more telomeric proximal breakpoint (n = 2), or more centromeric (n = 3) or more telomeric distal breakpoint (n = 3). One NP subject had a proximal nested 1.4 Mb deletion. COMT and TBX1 were deleted in all 44 subjects, and PRODH in 40 subjects (19 SZ, 21 NP). The results delineate proximal and distal breakpoint variants in 22q11DS. Neither deletion
extent nor PRODH haploinsufficiency appeared to explain the clinical expression of schizophrenia in the present study. Further studies are
needed to elucidate the molecular basis of schizophrenia and clinical heterogeneity in 22q11DS. |
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