Smallest Region Of Overlap Research Articles

Copy-Number Gains of HUWE1 Due to Replication- and Recombination-Based Rearrangements

We previously reported on nonrecurrent overlapping duplications at Xp11.22 in individuals with nonsyndromic intellectual disability (ID) harboring HSD17B10, HUWE1, and the microRNAs miR-98 and let-7f-2 in the smallest region of overlap. Here, we describe six additional individuals with nonsyndromic ID and overlapping microduplications that segregate in the families. High-resolution mapping of the 12 copy-number gains reduced the minimal duplicated region to the HUWE1 locus only. Consequently, increased mRNA levels weredetected for HUWE1, but not HSD17B10. Marker and SNP analysis, together with identification of two de novo events, suggested a paternally derived intrachromosomal duplication event. In four independent families, we report on a polymorphic 70 kb recurrent copy-number gain, which harbors part of HUWE1 (exon 28 to 3' untranslated region), including miR-98 and let-7f-2. Our findings thus demonstrate that HUWE1 is the only remaining dosage-sensitive gene associated with the ID phenotype. Junction and insilico analysis of breakpoint regions demonstrated simple microhomology-mediated rearrangements suggestive of replication-based duplication events. Intriguingly, in a single family, the duplication was generated through nonallelic homologous recombination (NAHR) with the use of HUWE1-flanking imperfect low-copy repeats, which drive this infrequent NAHR event. The recurrent partial HUWE1 copy-number gain was also generated through NAHR, but here, the homologous sequences used were identified as TcMAR-Tigger DNA elements, a template that has not yet been reported for NAHR. In summary, we showed that an increased dosage of HUWE1 causes nonsyndromic ID and demonstrated that the Xp11.22 region is prone to recombination- and replication-based rearrangements.

American Journal of Medical Genetics Part A: Volume 158A, Number 7, July 2012

AbstractCOVER FIGUREThe figure displays the map of the deletions in chromosomal band 1q44 identified by aCGH. Black horizontal bars indicate the deletions in the 11 patients with ID and seizures. The vertical region shaded in red indicates the smallest region of overlap (SRO) implicated in ID and seizures; yellow indicates the SRO implicated in microcephaly and blue, the SRO implicated in corpus callosum abnormalities. B. Detailed map of the proposed critical region for ID and seizures, which contains three candidate genes: HNRNPU, FAM36A and NCRNA00201. See article by Thierry et al. in this issue.

Spatial variation of the cooling lines in the Orion Bar fromHerschel/PACS

We present spatially resolved Herschel/PACS observations of the Orion Bar. We have characterise the emission of the far-infrared fine-structure lines of [CII] (158um), [OI] (63 and 145um), and [NII] (122um) that trace the gas local conditions. The observed distribution and variation of the lines are discussed in relation to the underlying geometry and linked to the energetics associated with the Trapezium stars. These observations enable us to map the spatial distribution of these fine-structure lines with a spatial resolution between 4" and 11" and covering a total square area of about 120"x105". The spatial profile of the emission lines are modelled using the radiative transfer code Cloudy. We find that the spatial distribution of the [CII] line coincides with that of the [OI] lines. The [NII] line peaks closer to the ionising star than the other three lines, but with a small region of overlap. We can distinguish several knots of enhanced emission within the Bar indicating the presence of an inhomogenous and structured medium. The emission profiles cannot be reproduced by a single photo-dissociation region, clearly indicating that, besides the Bar, there is a significant contribution from additional photo-dissociation region(s) over the area studied. The combination of both the [NII] and [OI] 145um lines can be used to estimate the [CII] emission and distinguish between its ionised or neutral origin. We have calculated how much [CII] emission comes from the neutral and ionised region, and find that at least 82% originates from the photo-dissocciation region. Together, the [CII] 158um and [OI] 63 and 145um lines account for 90% of the power emitted by the main cooling lines in the Bar (including CO, H2, etc...), with [OI] 63um alone accounting for 72% of the total.

Chromosome 15q24 microdeletion syndrome

Chromosome 15q24 microdeletion syndrome is a recently described rare microdeletion syndrome that has been reported in 19 individuals. It is characterized by growth retardation, intellectual disability, and distinct facial features including long face with high anterior hairline, hypertelorism, epicanthal folds, downslanting palpebral fissures, sparse and broad medial eyebrows, broad and/or depressed nasal bridge, small mouth, long smooth philtrum, and full lower lip. Other common findings include skeletal and digital abnormalities, genital abnormalities in males, hypotonia, behavior problems, recurrent infections, and eye problems. Other less frequent findings include hearing loss, growth hormone deficiency, hernias, and obesity. Congenital malformations, while rare, can be severe and include structural brain anomalies, cardiovascular malformations, congenital diaphragmatic hernia, intestinal atresia, imperforate anus, and myelomeningocele. Karyotypes are typically normal, and the deletions were detected in these individuals by array comparative genomic hybridization (aCGH). The deletions range in size from 1.7-6.1 Mb and usually result from nonallelic homologous recombination (NAHR) between paralogous low-copy repeats (LCRs). The majority of 15q24 deletions have breakpoints that localize to one of five LCR clusters labeled LCR15q24A, -B, -C, -D, and -E. The smallest region of overlap (SRO) spans a 1.2 Mb region between LCR15q24B to LCR15q24C. There are several candidate genes within the SRO, including CYP11A1, SEMA7A, CPLX3, ARID3B, STRA6, SIN3A and CSK, that may predispose to many of the clinical features observed in individuals with 15q24 deletion syndrome. The deletion occurred as a de novo event in all of the individuals when parents were available for testing. Parental aCGH and/or FISH studies are recommended to provide accurate genetic counseling and guidance regarding prognosis, recurrence risk, and reproductive options. Management involves a multi-disciplinary approach to care with the primary care physician and clinical geneticist playing a crucial role in providing appropriate screening, surveillance, and care for individuals with this syndrome. At the time of diagnosis, individuals should receive baseline echocardiograms, audiologic, ophthalmologic, and developmental assessments. Growth and feeding should be closely monitored. Other specialists that may be involved in the care of individuals with 15q24 deletion syndrome include immunology, endocrine, orthopedics, neurology, and urology. Chromosome 15q24 microdeletion syndrome should be differentiated from other genetic syndromes, particularly velo-cardio-facial syndrome (22q11.2 deletion syndrome), Prader-Willi syndrome, and Noonan syndrome. These conditions share some phenotypic similarity to 15q24 deletion syndrome yet have characteristic features specific to each of them that allows the clinician to distinguish between them. Molecular genetic testing and/or aCGH will be able to diagnose these conditions in the majority of individuals.Disease name and synonymsChromosome 15q24 deletion syndrome15q24 deletion syndrome15q24 microdeletion syndrome

High-resolution array CGH defines critical regions and candidate genes for microcephaly, abnormalities of the corpus callosum, and seizure phenotypes in patients with microdeletions of 1q43q44

Microdeletions of 1q43q44 result in a recognizable clinical disorder characterized by moderate to severe intellectual disability (ID) with limited or no expressive speech, characteristic facial features, hand and foot anomalies, microcephaly (MIC), abnormalities (agenesis/hypogenesis) of the corpus callosum (ACC), and seizures (SZR). Critical regions have been proposed for some of the more prominent features of this disorder such as MIC and ACC, yet conflicting data have prevented precise determination of the causative genes. In this study, the largest of pure interstitial and terminal deletions of 1q43q44 to date, we characterized 22 individuals by high-resolution oligonucleotide microarray-based comparative genomic hybridization. We propose critical regions and candidate genes for the MIC, ACC, and SZR phenotypes associated with this microdeletion syndrome. Three cases with MIC had small overlapping or intragenic deletions of AKT3, an isoform of the protein kinase B family. The deletion of only AKT3 in two cases implicates haploinsufficiency of this gene in the MIC phenotype. Likewise, based on the smallest region of overlap among the affected individuals, we suggest a critical region for ACC that contains ZNF238, a transcriptional and chromatin regulator highly expressed in the developing and adult brain. Finally, we describe a critical region for the SZR phenotype which contains three genes (FAM36A, C1ORF199, and HNRNPU). Although ~90% of cases in this study and in the literature fit these proposed models, the existence of phenotypic variability suggests other mechanisms such as variable expressivity, incomplete penetrance, position effects, or multigenic factors could account for additional complexity in some cases.

Characterization of a 8q21.11 Microdeletion Syndrome Associated with Intellectual Disability and a Recognizable Phenotype

We report eight unrelated individuals with intellectual disability and overlapping submicroscopic deletions of 8q21.11 (0.66-13.55 Mb in size). The deletion was familial in one and simplex in seven individuals. The phenotype was remarkably similar and consisted of a round face with full cheeks, a high forehead, ptosis, cornea opacities, an underdeveloped alae, a short philtrum, a cupid's bow of the upper lip, down-turned corners of the mouth, micrognathia, low-set and prominent ears, and mild finger and toe anomalies (camptodactyly, syndactyly, and broadening of the first rays). Intellectual disability, hypotonia, decreased balance, sensorineural hearing loss, and unusual behavior were frequently observed. A high-resolution oligonucleotide array showed different proximal and distal breakpoints in all of the individuals. Sequencing studies in three of the individuals revealed that proximal and distal breakpoints were located in unique sequences with no apparent homology. The smallest region of overlap was a 539.7 kb interval encompassing three genes: a Zinc Finger Homeobox 4 (ZFHX4), one microRNA of unknown function, and one nonfunctional pseudogen. ZFHX4 encodes a transcription factor expressed in the adult human brain, skeletal muscle, and liver. It has been suggested as a candidate gene for congenital bilateral isolated ptosis. Our results suggest that the 8q21.11 submicroscopic deletion represents a clinically recognizable entity and that a haploinsufficient gene or genes within the minimal deletion region could underlie this syndrome.

Genomic and clinical characteristics of six patients with partially overlapping interstitial deletions at 10p12p11

With the clinical implementation of genomic microarrays, the detection of cryptic unbalanced rearrangements in patients with syndromic developmental delay has improved considerably. Here we report the molecular karyotyping and phenotypic description of six new unrelated patients with partially overlapping microdeletions at 10p12.31p11.21 ranging from 1.0 to 10.6 Mb. The smallest region of overlap is 306 kb, which includes WAC gene, known to be associated with microtubule function and to have a role in cell division. Another patient has previously been described with a 10 Mb deletion, partially overlapping with our six patients. All seven patients have developmental delay and a majority of the patients have abnormal behaviour and dysmorphic features, including bulbous nasal tip, deep set eyes, synophrys/thick eyebrows and full cheeks, whereas other features varied. All patients also displayed various visual impairments and six out of seven patients had cardiac malformations. Taken together with the previously reported patient, our study suggests that the detected deletions may represent a new contiguous gene syndrome caused by dosage-sensitive genes that predispose to developmental delay.

Multimodal image registration using IECC as the similarity measure

The registration of images from positron emission tomography (PET) to those from magnetic resonance imaging (MRI) using mutual information is usually effective, but fails occasionally because of small region of overlap, low-activity defects in the PET image, difference in spatial resolution, etc. In this article, the authors propose the pixel-based individual entropy correlation coefficient (IECC) as a new, more accurate and more robust registration criterion. The authors compare it to the current criteria: Mutual information (MI), normalized mutual information (NMI), and the entropy correlation coefficient (ECC). The anatomical region to be registered was the head. A rigid-body registration was used; no deformation was employed. The authors established the effectiveness of IECC by both simulated data and clinical studies using brain fluorodeoxyglucose (FDG) PET and MRI. Both a normal-activity FDG model and a FDG model with a perfusion defect were used for the PET image. Reconstruction by both filtered backprojection and by ordered subset-expectation maximization was investigated. The mean errors and SDs of IECC were 1.17 +/- 0.85 mm for translation and 1.04 +/- 1.28 degrees for rotation in clinical PET. Those of MI, NMI, and ECC were 1.86 +/- 1.22, 1.86 +/- 0.96, and 1.68 +/- 4 1.05 mm for translations and 1.52 +/- 1.84 degrees, 1.74 +/- 1.68 degrees, and 1.70 +/- 1.90 degrees for rotations. The mean errors and SDs of IECC were 1.56 +/- 0.58 mm for translation and 1.46 +/- 1.66 degrees for rotation in clinical PET model with a 30% perfusion defect. Those of MI, NMI, and ECC were 2.81 +/- 1.41, 2.98 +/- 1.80, and 3.29 +/- 2.08 mm for translations and 3.34 +/- 3.800, 2.87 +/- 3.25 degrees, and 3.04 +/- 3.44 degrees for rotations. The mean errors and SDs of IECC were 1.79 +/- 1.04 mm for translation and 1.64 +/- 1.62 degrees for rotation in clinical PET model with a 50% perfusion defect. Those of MI, NMI, and ECC were 3.49 +/- 1.92, 3.57 +/- 2.22, and 3.49 +/- 1.89 mm for translations and 4.12 +/- 4.24 degrees, 3.62 +/- 4.87 degrees, and 3.44 +/- 3.80 degrees for rotations. The significant differences between IECC and each of the other three criteria were found for displacement misregistration in almost all parameters (p < 0.01). Accuracy of the IECC criterion was higher than that of the other criteria, usually in a statistically significant way.

A 5.3 Mb deletion in chromosome 18q12.3 as the smallest region of overlap in two patients with expressive speech delay

Interstitial 18q deletions encompassing band 18q12.3 define the del(18)(q12.2q21.1) syndrome. Usual manifestations are mild dysmorphic features, mental retardation, behaviour abnormalities and lack of serious malformation. Seizures have also been found. Recently, more specifically, impairment of expressive language has been reported. We report on two patients with de novo 18q interstitial deletions characterized by oligonucleotide array CGH. The smallest, a 5.3 Mb deletion (35.7–40.9 Mb) within band q12.3, was found in a 4-year-old girl who suffered mainly from expressive dysphasia. A larger 9.5 Mb deletion (34.6–43.9 Mb) was observed in a 20-year-old man with a more severe clinical picture including seizures and limited speech. Among the four genes located in the 5.3 Mb region, RIT2 (Ras-like without CAAX 2) and SYT4 (synaptotagmin IV), both strongly expressed in the brain, are pointed out as likely candidate genes for language development.

New cases and refinement of the critical region in the 1q41q42 microdeletion syndrome

Microdeletions of 1q41q42 have recently been classified as a syndrome. Features include significant developmental delay and characteristic dysmorphic features as well as cleft palate, clubfeet, seizures, and short stature in some individuals, with a clinical diagnosis of Fryns syndrome in two individuals with congenital diaphragmatic hernia at the severe end of the spectrum. The gene DISP1, which is involved in sonic hedgehog signaling, has been proposed as a candidate for the midline defects in this syndrome. We undertook a genotype–phenotype analysis of seven previously unreported individuals with deletions of 1q41q42 that range from 777 kb to 6.87 Mb. Three of the individuals in our cohort do not display the major features of the syndrome and have more proximal deletions that only overlap with the previously described 1q41q42 smallest region of overlap (SRO) at DISP1. One individual with several features of the syndrome has a more distal deletion that excludes DISP1. The three remaining individuals have larger deletions that include the entire SRO and demonstrate features of the microdeletion syndrome. Confounding genotype–phenotype correlations, one of the small deletions involving DISP1 was inherited from a phenotypically normal parent. DISP1 haploinsufficiency may not be solely responsible for the major features of 1q41q42 microdeletion syndrome, and other genes in the SRO likely play a role in the phenotype. Additionally, some features present in a minority of individuals, such as Pelger–Huët anomaly, may be attributed to deletions of genes outside of the SRO.

Genotype–phenotype correlation in eight new patients with a deletion encompassing 2q31.1

Microdeletions of the 2q31.1 region are rare. We present the clinical and molecular findings of eight previously unreported patients with overlapping deletions in 2q31.1. The patients have a variable clinical phenotype and present with developmental delay (7/8), growth retardation (5/8), seizures (2/8) and a craniofacial dysmorphism consisting of microcephaly (4/8), short palpebral fissures (7/8), broad eyebrows with lateral flare (7/8), low-set ears with thickened helices and lobules (5/8), and micrognathia (6/8). Additional congenital anomalies were noted, including limb abnormalities (8/8), heart defects (3/8), genital anomalies (3/8), and craniosynostosis (1/8). Six of these microdeletions, ranging in size from 1.24 to 8.35 Mb, were identified by array CGH, one larger deletion (19.7 Mb) was detected by conventional karyotyping and further characterized by array CGH analysis. The smallest region of overlap in all eight patients spans at most 88 kb and includes only the WIPF1 gene. This gene codes for the WAS/WASL interacting protein family member 1. The patients described here do not present with clinical signs of the Wiskott-Aldrich syndrome and the deletion of this single gene does not allow explaining the phenotype in our patients. It is likely that the deletion of different but overlapping sets of genes from 2q31 is responsible for the clinical variability in these patients. To further dissect the complex phenotype associated with deletions in 2q31, additional patients with overlapping phenotypes should be examined with array CGH. This should help to link particular phenotypes to specific genes, and add to our understanding of the underlying developmental processes.

Identification of Uncommon Recurrent Potocki-Lupski Syndrome-Associated Duplications and the Distribution of Rearrangement Types and Mechanisms in PTLS

Nonallelic homologous recombination (NAHR) can mediate recurrent rearrangements in the human genome and cause genomic disorders. Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are genomic disorders associated with a 3.7 Mb deletion and its reciprocal duplication in 17p11.2, respectively. In addition to these common recurrent rearrangements, an uncommon recurrent 5 Mb SMS-associated deletion has been identified. However, its reciprocal duplication predicted by the NAHR mechanism had not been identified. Here we report the molecular assays on 74 subjects with PTLS-associated duplications, 35 of whom are newly investigated. By both oligonucleotide-based comparative genomic hybridization and recombination hot spot analyses, we identified two cases of the predicted 5 Mb uncommon recurrent PTLS-associated duplication. Interestingly, the crossovers occur in proximity to a recently delineated allelic homologous recombination (AHR) hot spot-associated sequence motif, further documenting the common hot spot features shared between NAHR and AHR. An additional eight subjects with nonrecurrent PTLS duplications were identified. The smallest region of overlap (SRO) for all of the 74 PTLS duplications examined is narrowed to a 125 kb interval containing only RAI1, a gene recently further implicated in autism. Sequence complexities consistent with DNA replication-based mechanisms were identified in four of eight (50%) newly identified nonrecurrent PTLS duplications. Our findings of the uncommon recurrent PTLS-associated duplication at a relative prevalence reflecting the de novo mutation rate and the distribution of 17p11.2 duplication types in PTLS reveal insights into both the contributions of new mutations and the different underlying mechanisms that generate genomic rearrangements causing genomic disorders.

Optical Characterization of All-Magnetic NOT Gate Operation in Vortex Rings

We have demonstrated deterministic operation of inverters (NOT gates) using vortex magnetization states in pairs of linked 5 mum diameter permalloy rings with a small region of overlap. The input ring is clipped so that the state can be controlled by global fields, and is designed to switch at lower fields than the unclipped output ring, which then inverts the logical state of the input. Optical coatings over half of each ring provide distinct magnetooptic Kerr effect (MOKE) signatures for saturation, clockwise, and counterclockwise states in our focused beam system. We demonstrate that excessive overlap between the rings leads to overall shape anisotropy dominating the behavior of the structure.

High-Resolution Genomic Profiling of Carboplatin Resistance in Early-Stage Epithelial Ovarian Carcinoma

Chemotherapy resistance remains a major obstacle to successful treatment of ovarian cancer patients. Therefore, increased knowledge of underlying mechanisms and identification of predictive factors are of great importance. Standard treatment for ovarian carcinoma is surgery followed by platinum-based chemotherapy. In this study, we aimed to search for genes or genomic regions involved in platinum resistance in ovarian carcinoma. Array-based comparative genomic hybridization (CGH) was used to identify genetic alterations in 32 early-stage epithelial ovarian carcinomas homogeneously treated with single-agent carboplatin. The arrays contain 33,370 bacterial artificial chromosome (BAC) clones and form a contiguous and tiling coverage of the human genome with an average resolution of ∼100 kb. We found certain genetic changes associated with carboplatin response. Gains in 1q25.1–q41 were significantly more frequent in carboplatin-resistant tumours. In this region, we further detected two smallest regions of overlap (SRO) at 1q25.2 and 1q32.2 (∼690 and ∼830 kb in size, respectively). Interestingly, we found some regions that were lost exclusively in the sensitive tumours 17q24.1, Xq21.33–q22.1, and 6 regions in 15q. We also detected genetic differences with regard to histologic subtype. Gain in 8q was found highly associated with serous and clear cell subtypes, and an SRO was identified at 8q24.22–q24.23. The genomic regions found altered in this study confirm some of our previous metaphase CGH results. The alteration found in chromosome arm 1q was verified and specified, and is therefore of great interest as a candidate for predictive markers. Identifying predictive markers of chemosensitive and chemoresistant disease would greatly help in the choice of chemotherapy in the clinic, and thus improve treatment of women with ovarian cancer.

Expression of TSLC1, a candidate tumor suppressor gene mapped to chromosome 11q23, is downregulated in unfavorable neuroblastoma without promoter hypermethylation

Although it has been well documented that loss of human chromosome 11q is frequently observed in primary neuroblastomas, the smallest region of overlap (SRO) has not yet been precisely identified. Previously, we performed array-comparative genomic hybridization (array-CGH) analysis for 236 primary neuroblastomas to search for genomic aberrations with high-resolution. In our study, we have identified the SRO of deletion (10-Mb or less) at 11q23. Within this region, there exists a TSLC1/IGSF4/CADM1 gene (Tumor suppressor in lung cancer 1/Immunoglobulin superfamily 4/Cell adhesion molecule 1), which has been identified as a putative tumor suppressor gene for lung and some other cancers. Consistent with previous observations, we have found that 35% of primary neuroblastomas harbor loss of heterozygosity (LOH) on TSLC1 locus. In contrast to other cancers, we could not detect the hypermethylation in its promoter region in primary neuroblastomas as well as neuroblastoma-derived cell lines. The clinicopathological analysis demonstrated that TSLC1 expression levels significantly correlate with stage, Shimada's pathological classification, MYCN amplification status, TrkA expression levels and DNA index in primary neuroblastomas. The immunohistochemical analysis showed that TSLC1 is remarkably reduced in unfavorable neuroblastomas. Furthermore, decreased expression levels of TSLC1 were significantly associated with a poor prognosis in 108 patients with neuroblastoma. Additionally, TSLC1 reduced cell proliferation in human neuroblastoma SH-SY5Y cells. Collectively, our present findings suggest that TSLC1 acts as a candidate tumor suppressor gene for neuroblastoma.

QUANTITATIVE ANALYSIS OF EXPOSURE OF STAGED ORBITOZYGOMATIC AND RETROSIGMOID CRANIOTOMIES FOR LESIONS OF THE CLIVUS WITH SUPRATENTORIAL EXTENSION

A two-stage approach using orbitozygomatic (OZ) and retrosigmoid (RS) craniotomies is one option for the management of petroclival lesions with supratentorial extension. The goal of this study was to investigate the supratentorial and infratentorial exposures of the clivus obtained through this staged approach. Formalin-fixed, silicon-injected specimens underwent stereotactic imaging. Six paired OZ and RS craniotomies were performed. Neuronavigation was used to determine the areas and limits of exposure and to plot these areas on three-dimensional reconstructions of the skull base. The mean area of exposure of the parasellar region and clivus through the OZ craniotomy was 640 +/- 75 mm. Visualization of the parasellar region, cavernous sinus, and upper cranial nerves was achieved. The ventral brainstem corresponding to the cranial quarter of the clivus was visualized. The mean area of exposure of the clivus and petrous bone through the RS was 1930 +/- 250 mm. In the cranial quarter of the clivus, there was a small region of overlap in exposure between the two craniotomies. The limits of exposure are described. OZ and RS craniotomies provide complementary exposure with limited redundancy. Significant visualization of the parasellar region, clivus, and surrounding bony landmarks is obtained. The primary limitation is exposure of the contralateral half of Zones II and III of the clivus. This strategy represents a reasonable option for accessing paracentral petroclival lesions with a supratentorial extension.

On dipole moments of overlapping atoms. Application to H in 1 s, 2 s, and 2po states

The dipole moments of two overlapping H atoms in the dissimilar states 1 s, 2 s and 2p$_{o}$ were calculated for both the triplet (destructive overlap) and the singlet (constructive overlap) states at large separations. The results are based on the Heitler-London method, using elliptical coordinates with the nucleus of the larger, more diffused orbital, located at a on the Z-axis of the coordinate system, and the nucleus of the smaller, less diffused orbital, located at b on the Z-axis. The origin of the coordinate system is midway between a and b. We find it instructive to identify three types of moments - a moment associated with the orbital on a, a moment associated with the orbital on b, and the overall moment, which is the sum of these two. It is shown that in the region of small overlap the calculated values of the dipoles on a and on b point towards each other in the triplet state, and away from each other in the singlet state. In every case, the total or net dipole moment points from the more diffused orbital towards the more compact orbital. The absolute value of the more diffused orbital is always found to be greater than of the more rigid orbital.

Loss of expression of chromosome 16q genes DPEP1 and CTCF in lobular carcinoma in situ of the breast

Loss of the chromosomal material at 16q is the most frequent genetic event in invasive and in situ (LCIS) lobular carcinoma of the breast. However, the smallest region of overlap at 16q is not restricted to just the CDH1 locus harbouring E-cadherin, suggesting that neighbouring genes might be involved in the development and progression of these tumours. Potential novel tumour suppressor genes (TSG) at 16q include CCCTC-binding factor (CTCF), Decreased Expression in Renal and Prostate Cancer (DERPC) and Dipeptidase 1 (DPEP1). The aim of this study is to assess the expression of these genes in LCIS and compare them with normal breast, using CDH1 as a control, in order to evaluate their role as TSGs. Cells from LCIS cases and normal breast lobules were microdissected and expression of target genes were quantified using real-time PCR. In addition, immunohistochemistry (IHC) for E-cadherin and CTCF was performed on paraffin processed LCIS (n=49) and normal breast cases. All LCIS showed negative expression of E-cadherin. Similar to CDH1, CTCF and DPEP1 gene expression was significantly lower in LCIS cases compared with normal cases (P<0.05). CTCF IHC expression showed significant reduction in LCIS compared to normal parenchymal cells. However, there was no difference in expression of DERPC between LCIS and normal breast tissue. In addition to CDH1, loss of CTCF and DPEP1 gene expression suggest they are possible TSG in breast cancer and may, similar to CDH1, be potentially utilised as markers of predisposition of women diagnosed with LCIS.

Paternal deletion 6q24.3: A new congenital anomaly syndrome associated with intrauterine growth failure, early developmental delay and characteristic facial appearance

Deletions of the long arm of chromosome 6 are relatively uncommon and to date minimal genotype-phenotype correlations have been observed. We report on three unrelated patients with de novo paternal interstitial deletions of 6q24.3. FISH mapping was used to delineate the minimal region of overlap between these three patients. Although all three patients had different size deletions and different breakpoints, two of the patients shared a 2.5 Mb region of overlap and strikingly similar facial features including a triangular face, frontal bossing with metopic prominence, short and upward-slanting palpebral fissures, asymmetry of upper eyelids, hooded eyelids, shallow orbits, prominent inferior orbital crease, wide mouth, and long and flat philtrum. They also had redundant skin, joint laxity, a small thorax, and early developmental delay. The smallest region of overlap between all three patients was a region of deletion less than 1 Mb; all had a history of IUGR and postnatal short stature without overt radiologic skeletal anomalies. The dysmorphic features, early developmental and growth delay may be due to the hemizygous state for one of the genes in the deleted region of two of the patients or to a long range effect of the deletion on expression of other genes. In addition, since imprinted genes have been reported in this region, paternal deletion of an imprinted gene in all three patients may contribute to the growth phenotype. We propose that this is a new congenital malformation syndrome associated with a paternal deletion of 6q24.3.

Phyllodes tumors of the breast segregate in two groups according to genetic criteria

AbstractPhyllodes tumors are rare fibroepithelial tumors of the breast. The pathologic grading of phyllodes tumors based on the aspect of the stromal component, is divided into 2 or 3 grades according to the system used. To determine whether genetic markers could be of use for improving the classification of phyllodes tumors and to provide a better knowledge of the genetic alterations in these tumors, we analyzed chromosomal changes detected by comparative genomic hybridization (CGH) in comparison with histological data, in a series of 30 cases. Recurrent chromosome imbalances were observed in 55, 91 and 100% of benign, borderline and malignant phyllodes tumors, respectively. The mean number of chromosome changes was one in benign, six in borderline, and six in malignant phyllodes tumors. Most frequent genetic imbalances were +1q (12/30), −13q (7/30), −6q (9/30), +5 (9/30) and −10p (8/30). Gains of 1q, present in only one of nine benign tumors, were found in 11/21 (51%) borderline or malignant tumors. Losses of 13q have 13q14.2 as smallest region of overlap, suggesting that the RB1 gene could be the target of deletions. Amplifications of 12q14, involving the MDM2 locus, and of 8p24, involving the MYC gene, were observed in one case each. Borderline and malignant phyllodes tumors could not be differentiated on the basis of their genomic imbalances (presence and number of chromosomal changes, presence of 1q gain and/or 13q loss). Conversely, benign tumors could be significantly differentiated from the group composed of borderline and malignant tumors (P<0.01). This study reveals two distinct patterns of genomic imbalance in phyllodes tumors: benign, with none or a few chromosome changes and malignant, with numerous recurrent chromosomal changes, in particular 1q gain and 13q loss. Helpful additional pathological criteria for differentiating the two genetic groups of phyllodes tumors are the nuclear size and the mitotic rate.