Discovery of previously unidentified genomic disorders from the duplication architecture of the human genome.

Genomic disorders are characterized by the presence of flanking segmental duplications that predispose these regions to recurrent rearrangement. Based on the duplication architecture of the genome, we investigated 130 regions that we hypothesized as candidates for previously undescribed genomic disorders. We tested 290 individuals with mental retardation by BAC array comparative genomic hybridization and identified 16 pathogenic rearrangements, including de novo microdeletions of 17q21.31 found in four individuals. Using oligonucleotide arrays, we refined the breakpoints of this microdeletion, defining a 478-kb critical region containing six genes that were deleted in all four individuals. We mapped the breakpoints of this deletion and of four other pathogenic rearrangements in 1q21.1, 15q13, 15q24 and 17q12 to flanking segmental duplications, suggesting that these are also sites of recurrent rearrangement. In common with the 17q21.31 deletion, these breakpoint regions are sites of copy number polymorphism in controls, indicating that these may be inherently unstable genomic regions.

Pain relief for the removal of femoral sheath in interventional cardiology adult patients.

BACKGROUND: There is considerable variation in use of pain relief for managing pain or discomfort of femoral sheath removal. Efficacy of pain relief to promote comfort during this procedure or to reduce the incidence of vascular and procedural complications has not been established. OBJECTIVES: Assess efficacy of pain relief used to manage pain of femoral sheath removal in adults after interventional cardiology.Determine if pain relief influences rate of complications associated with this procedure. SEARCH STRATEGY: Databases searched in August 2007: Cochrane Pain, Palliative and Supportive Care Group Trials Register, Cochrane Heart Group Trials Register, Cochrane CENTRAL, MEDLINE, EMBASE, CINAHL, PubMed, Australia's Australasian Medical Index, National Research Centre, Web of Knowledge and Digital Dissertations. SELECTION CRITERIA: Randomised studies comparing opioid, local anaesthetic, anxiolytic, no treatment or placebo administered for alleviation of pain or discomfort of the femoral sheath removal procedure, were sought. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial quality and extracted data. Weighted mean differences (WMD) were calculated where meta-analysis of pain score data was feasible. Adverse effects information was collected. MAIN RESULTS: Four trials involving 971 participants were included. All results were reported using a zero to ten pain scale. Three trials (four treatment arms) involving 498 participants compared subcutaneous lignocaine with control; with no significant difference between pain scores; WMD 0.12 (95% CI -0.46 to 0.69). Two trials (three treatment arms) involving 399 participants compared intravenous pain regimens with control. A significant reduction in pain score with an intravenous pain regimen (opioid and anxiolytic) was observed when compared with placebo; WMD -0.90 (95% CI -1.54 to -0.27). One study involving 60 participants compared levobupivacaine with placebo. Longer-acting local anaesthetic significantly lowered pain score by -1.10 (95% CI -1.26 to -0.94). Data is insufficient to identify any influence of pain regimens on incidence of vascular and procedural complications. No trials reported appropriate blinding for treatment arms. The largest trial, comprising 661 participants was unblinded with a quality score of two out of five. AUTHORS' CONCLUSIONS: Intravenous pain regimens and levobupivacaine may have greater efficacy when compared to control for the management of pain related to femoral sheath removal. However, a definitive study is still required because the clinical difference is small. There is no evidence to support the use of subcutaneous lignocaine for the relief of femoral sheath removal related pain. There is insufficient evidence to determine if pain relief influences the rate of complications.

Characterization of a recurrent 15q24 microdeletion syndrome.

We describe multiple individuals with mental retardation and overlapping de novo submicroscopic deletions of 15q24 (1.7-3.9 Mb in size). High-resolution analysis showed that in three patients both proximal and distal breakpoints co-localized to highly identical segmental duplications (>51 kb in length, > 94% identity), suggesting non-allelic homologous recombination as the likely mechanism of origin. Sequencing studies in a fourth individual provided base pair resolution and showed that both breakpoints in this case were located in unique sequence. Despite the differences in the size and location of the deletions, all four individuals share several major features (growth retardation, microcephaly, digital abnormalities, hypospadias and loose connective tissue) and resemble one another facially (high anterior hair line, broad medial eyebrows, hypertelorism, downslanted palpebral fissures, broad nasal base, long smooth philtrum and full lower lip), indicating that this represents a novel syndrome caused by haploinsufficiency of one or more dosage-sensitive genes in the minimal deletion region. Our results define microdeletion of 15q24 as a novel recurrent genomic disorder.

Chromosome 7p disruptions in Silver Russell syndrome: delineating an imprinted candidate gene region.

Silver-Russell syndrome (SRS) is characterised by pre- and postnatal growth restriction (PNGR) and additional dysmorphic features including body asymmetry and fifth finger clinodactyly. The syndrome is genetically heterogeneous, with a number of chromosomes implicated. However, maternal uniparental disomy for chromosome 7 has been demonstrated in up to 10% of all cases. Three SRS probands have previously been described with a maternally inherited duplication of 7p11.2-p13, defining this as a candidate region. Over-expression of a maternally transcribed, imprinted gene with growth-suppressing activity located within the duplicated region, or breakpoint disruption of genes or regulatory sequences, may account for the phenotype in these cases. Here we describe two additional SRS patients and four probands with PNGR with a range of cytogenetic disruptions of 7p, including duplications, pericentric inversions and a translocation. An incomplete contig consisting of 80 PACs and BACs from the centromere to 7p14 was constructed. Individual clones from this contig were used as FISH probes to map the breakpoints in the six new cases and the three duplication probands previously described. Our data provide further evidence for a candidate SRS region at 7p11.1-p14. A common breakpoint region was identified within 7p11.2 in all nine cases, pinpointing this specific interval. The imprinting status of genes within the 7p11.1-p14 region flanked by the most extreme breakpoints have been analysed using both somatic cell hybrids containing a single full-length maternally or paternally derived chromosome 7 and expressed single nucleotide polymorphisms in paired fetal and maternal samples.