Breakpoint Associated with a novel 2.3 Mb deletion in the VCFS region of 22q11 and the role of Alu (SINE) in recurring microdeletions

BACKGROUND: Chromosome 22q11.2 region is highly susceptible to rearrangement, specifically deletions that give rise to a variety of genomic disorders including velocardiofacial or DiGeorge syndrome. Individuals with this 22q11 microdeletion syndrome are at a greatly increased risk to develop schizophrenia. METHODS: Genotype analysis was carried out on the DNA from a patient with the 22q11 microdeletion using genetic markers and custom primer sets to define the deletion. Bioinformatic analysis was performed for molecular characterization of the deletion breakpoint sequences in this patient. RESULTS: This 22q11 deletion patient was established to have a novel 2.3 Mb deletion with a proximal breakpoint located between genetic markers RH48663 and RH48348 and a distal breakpoint between markers D22S1138 and SHGC-145314. Molecular characterization of the sequences at the breakpoints revealed a 270 bp shared sequence of the breakpoint regions (SSBR) common to both ends that share >90% sequence similarity to each other and also to short interspersed nuclear elements/Alu elements. CONCLUSION: This Alu sequence like SSBR is commonly in the proximity of all known deletion breakpoints of 22q11 region and also in the low copy repeat regions (LCRs). This sequence may represent a preferred sequence in the breakpoint regions or LCRs for intra-chromosomal homologous recombination mechanisms resulting in common 22q11 deletion

Search for copy number variants in chromosomes 15q11-q13 and 22q11.2 in obsessive compulsive disorder

<p>Abstract</p> <p>Background</p> <p>Obsessive-compulsive disorder (OCD) is a clinically and etiologically heterogeneous syndrome. The high frequency of obsessive-compulsive symptoms reported in subjects with the 22q11.2 deletion syndrome (DiGeorge/velocardiofacial syndrome) or Prader-Willi syndrome (15q11-13 deletion of the paternally derived chromosome), suggests that gene dosage effects in these chromosomal regions could increase risk for OCD. Therefore, the aim of this study was to search for microrearrangements in these two regions in OCD patients.</p> <p>Methods</p> <p>We screened the 15q11-13 and 22q11.2 chromosomal regions for genomic imbalances in 236 patients with OCD using multiplex ligation-dependent probe amplification (MLPA).</p> <p>Results</p> <p>No deletions or duplications involving 15q11-13 or 22q11.2 were identified in our patients.</p> <p>Conclusions</p> <p>Our results suggest that deletions/duplications of chromosomes 15q11-13 and 22q11.2 are rare in OCD. Despite the negative findings in these two regions, the search for copy number variants in OCD using genome-wide array-based methods is a highly promising approach to identify genes of etiologic importance in the development of OCD.</p

Visuospatial working memory in children and adolescents with 22q11.2 deletion syndrome; an fMRI study

22q11.2 deletion syndrome (22q11DS) is a genetic disorder associated with a microdeletion of chromosome 22q11. In addition to high rates of neuropsychiatric disorders such as schizophrenia and attention deficit hyperactivity disorder, children with 22q11DS have a specific neuropsychological profile with particular deficits in visuospatial and working memory. However, the neurobiological substrate underlying these deficits is poorly understood. We investigated brain function during a visuospatial working memory (SWM) task in eight children with 22q11DS and 13 healthy controls, using fMRI. Both groups showed task-related activation in dorsolateral prefrontal cortex (DLPFC) and bilateral parietal association cortices. Controls activated parietal and occipital regions significantly more than those with 22q11DS but there was no significant between-group difference in DLPFC. In addition, while controls had a significant age-related increase in the activation of posterior brain regions and an age-related decrease in anterior regions, the 22q11DS children showed the opposite pattern. Genetically determined differences in the development of specific brain systems may underpin the cognitive deficits in 22q11DS, and may contribute to the later development of neuropsychiatric disorders

Controversies concerning the diagnosis and treatment of bipolar disorder in children

This commentary grows out of an interdisciplinary workshop focused on controversies surrounding the diagnosis and treatment of bipolar disorder (BP) in children. Although debate about the occurrence and frequency of BP in children is more than 50 years old, it increased in the mid 1990s when researchers adapted the DSM account of bipolar symptoms to diagnose children. We offer a brief history of the debate from the mid 90s through the present, ending with current efforts to distinguish between a small number of children whose behaviors closely fit DSM criteria for BP, and a significantly larger number of children who have been receiving a BP diagnosis but whose behaviors do not closely fit those criteria. We agree with one emerging approach, which gives part or all of that larger number of children a new diagnosis called Severe Mood Dysregulation or Temper Dysregulation Disorder with Dysphoria

Developmental malformation of the corpus callosum: a review of typical callosal development and examples of developmental disorders with callosal involvement

This review provides an overview of the involvement of the corpus callosum (CC) in a variety of developmental disorders that are currently defined exclusively by genetics, developmental insult, and/or behavior. I begin with a general review of CC development, connectivity, and function, followed by discussion of the research methods typically utilized to study the callosum. The bulk of the review concentrates on specific developmental disorders, beginning with agenesis of the corpus callosum (AgCC)—the only condition diagnosed exclusively by callosal anatomy. This is followed by a review of several genetic disorders that commonly result in social impairments and/or psychopathology similar to AgCC (neurofibromatosis-1, Turner syndrome, 22q11.2 deletion syndrome, Williams yndrome, and fragile X) and two forms of prenatal injury (premature birth, fetal alcohol syndrome) known to impact callosal development. Finally, I examine callosal involvement in several common developmental disorders defined exclusively by behavioral patterns (developmental language delay, dyslexia, attention-deficit hyperactive disorder, autism spectrum disorders, and Tourette syndrome)

Effects of the antiglucocorticoid RU 38486 on the induction of learned helpless behavior in Sprague-Dawley rats

Learned helplessness (LH) is induced by exposure to an inescapable or uncontrollable stressor which results in an inability to escape or avoid the same stressor when subsequently presented in a different context. In order to understand which central mechanisms may influence the expression of the learned helpless phenotype, we have pursued an experimental approach that seeks to elucidate the behavioral effects of glucocorticoid (GC) hormones in this animal model of depression. We have previously shown that the induction of LH behavior is enhanced by adrenalectomy, an effect that is reversed by corticosterone. In this study, our aim was to attempt to locate CNS sites responsible for the observed effects of glucocorticoids on learned helpless behavior by introducing the type II GC receptor antagonist, RU 38486 to discrete brain regions. We did not observe a significant effect in LH with acute systemic, acute dentate gyrus or intracerebroventricular injection of RU 38486 in contrast to previous studies using the Porsolt swim test, another animal model of depression. However, we were able to observe a significant change upon chronic administration to the dentate gyrus. These findings suggest that glucocorticoids exert a long-term influence on stress-induced behavior, presumably by affecting glucocorticoid responsive genes in the dentate gyrus

Hippocampal neuropeptide Y mRNA is reduced in a strain of learned helpless resistant rats

The learned helpless rat is considered to be one of the better animal models of depression. A genetically inbred strain with a high vulnerability to develop helplessness (LH), as well as a highly resistant strain (NLH) have both been developed. Since the brain peptide neuropeptide Y (NPY) is involved in the regulation of a number of behaviors known to be altered in clinical depression as well as in learned helplessness, we measured the relative level of NPY mRNA in the hippocampus and cortex of control Sprague Dawley (SD), LH and NLH rats. We find that NLH rats have approximately a 30-35% decrease in basal hippocampal NPY mRNA compared with SD and LH rats. By contrast, cortical NPY mRNA and hippocampal pre-proenkephalin and somatostatin mRNA levels were not significantly different in the 3 strains. The data suggest that the regulation of NPY gene expression may be involved in the reduced vulnerability of NLH rats to develop learned helplessness