Molecular diagnosis of 22q11.2 deletion and duplication by multiplex ligation dependent probe amplification.

22q11 Deletion syndrome (22q11DS) is the most common microdeletion syndrome in humans, occurring with an incidence of 1 in 4,000. In most cases the submicroscopic deletion spans 3 Mb, but there are a number of other overlapping and non-overlapping deletions that generate a similar phenotype. The majority of the 22q11.2 microdeletions can be ascertained using a standard fluorescence in situ hybridization (FISH) assay probing for TUPLE1 or N25 on 22q11.2. However, this test fails to detect deletions that are either proximal or distal to the FISH probes, and does not provide any information about the length of the deletion. In order to increase the detection rate of 22q11.2 deletion and to better characterize the size and position of such deletions we undertook a study of 22q11.2 cases using multiplex ligation dependent probe amplification (MLPA). We used MLPA to estimate the size of the 22q11.2 deletions in 51 patients positive for TUPLE1 or N25 (FISH) testing, and to investigate 12 patients with clinical features suggestive of 22q11DS and negative FISH results. MLPA analysis confirmed a microdeletion in all 51 FISH-positive samples as well as microduplications in three samples. Further, it allowed us to delineate deletions not previously detected using standard clinical FISH probes in 2 of 12 subjects with clinical features suggestive of 22q11DS. We conclude that MLPA is a cost-effective and accurate diagnostic tool for 22q11DS with a higher sensitivity than FISH alone. Additional advantages of MLPA testing in our study included determination of deletion length and detection of 22q11.2 duplications. (c) 2007 Wiley-Liss, Inc.

Assessment and medication management of paediatric obsessive-compulsive disorder.

Paediatric obsessive-compulsive disorder (OCD) is a common, yet under-recognized, neuropsychiatric illness in both clinical and community settings. Symptoms tend to be hidden or misunderstood by affected youth, and parents may inadvertently accommodate OCD, thus worsening its severity. These symptoms may include compulsive reassurance seeking, confessing and 'just right' rituals, in addition to more classic OCD behaviours. Fortunately, numerous psychometric measures are available to assist in clinical assessment of this disorder and its sequelae. Once properly diagnosed, paediatric OCD is highly treatable with empirically proven approaches including cognitive-behaviour therapy (CBT) and serotonin reuptake inhibitor (SRI) medications. Clinically meaningful symptom improvement is the norm following these strategies, although full remission is not, as symptoms tend to wax and wane over time. Paediatric OCD is highly co-morbid with other anxiety disorders, tic disorders, depression and attention-deficit hyperactivity disorder, which also require specific attention. For moderate to severe OCD, an interdisciplinary approach combining individual and family CBT with SRI trials is recommended. For severe treatment-refractory illness, early evidence supports the benefit of augmenting agents, such as atypical antipsychotics and potentially those with glutamatergic activity. Clinical outcome assessment in paediatric OCD should always include broad domains of individual and family functioning, in addition to symptom improvement.

Anxiety Disorders and Perceptual Disturbances in Adolescents with 22q11.2 Deletion Syndrome Treated with SSRI: A Case Series.

INTRODUCTION: Psychotic symptoms are highly prevalent in adolescents with 22q11.2 Deletion Syndrome (22qDS), with as many as half reporting transient psychotic symptoms. Anxiety is also commonly seen in this population, and patients frequently report both psychotic symptoms and anxiety. OBJECTIVE: To describe the psychiatric presentation, course and management of primary anxiety disorders in patients with 22qDS who also presented with isolated perceptual disturbances. METHOD: This report describes a 24-month clinical follow-up of three patients with 22qDS who were seen in the Medical Psychiatry clinic at the Hospital for Sick Children (Toronto, Canada). RESULTS: Patients presented with primary anxiety disorders and perceptual disturbances. Patients were placed on selective serotonin reuptake inhibitor only, with improvement of both anxiety and perceptual disturbances being noted. CONCLUSIONS: Some patients with 22qDS who present with psychotic symptoms do not develop a psychotic disorder; therefore, the use of antipsychotics for every child or adolescent with 22qDS who experience psychotic symptoms is debatable. Long-term follow-up, phenomenological and treatment efficacy studies in larger samples are needed to determine optimal treatment of psychotic symptoms in children and adolescents with 22qDS.

Molecular characterization of deletion breakpoints in adults with 22q11 deletion syndrome.

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.