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1.  Differential Copy Number Aberrations in Novel Candidate Genes Associated with Progression from In Situ to Invasive Ductal Carcinoma of the Breast 
Genes, chromosomes & cancer  2012;51(12):1067-1078.
Only a minority of intraductal carcinomas of the breast give rise to stromally invasive disease. We microdissected 206 paraffin blocks representing 116 different cases of low grade DCIS. Fifty-five were pure DCIS cases without progression to invasive carcinoma. Sixty-one cases had a small invasive component. DNA was extracted from microdissected sections and hybridized to high density BAC arrays. Array comparative genomic hybridization (aCGH) analysis of 118 hybridized DNA samples yielded data on 69 samples that were suitable for further statistical analysis. This cohort included 20 pure DCIS cases (PD), 25 mixed DCIS (MD), and 24 mixed invasive carcinoma samples (MI). Pure DCIS cases had a higher frequency of DNA copy number changes than mixed DCIS cases, and the latter had similar DNA profiles compared to paired invasive carcinomas. Copy number changes on 13 chromosomal arms occurred at different rates in PD versus MD lesions. Eight of 19 candidate genes residing at those loci were confirmed to have differential copy number changes by quantitative PCR. NCOR2/SMRT and NR4A1 (both on 12q), DYNLRB2 (16q), CELSR1, UPK3A and ST13 (all on 22q) were more frequently amplified in PD. Moreover, NCOR2, NR4A1 and DYNLRB2 showed more frequent copy number losses in MD. GRAP2 (22q) was more often amplified in MD, whereas TAF1C (16q) was more commonly deleted in PD. A multi-gene model comprising these candidate genes discriminated between PD and MD lesions with high accuracy. These findings suggest that the propensity to invade the stroma may be encoded in the genome of intraductal carcinomas.
doi:10.1002/gcc.21991
PMCID: PMC3465468  PMID: 22887771
2.  Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region 
Journal of Medical Genetics  2007;44(7):448-451.
A 4.3 Mb duplication of chromosome 21 bands q22.13–q22.2 was diagnosed by interphase fluorescent in‐situ hybridisation (FISH) in a 31‐week gestational age baby with cystic hygroma and hydrops; the duplication was later found in the mother and in her 8‐year‐old daughter by the same method and confirmed by array comparative genomic hybridisation (aCGH). All had the facial gestalt of Down syndrome (DS). This is the smallest accurately defined duplication of chromosome 21 reported with a DS phenotype. The duplication encompasses the gene DYRK1 but not DSCR1 or DSCAM, all of which have previously been implicated in the causation of DS. Previous karyotype analysis and telomere screening of the mother, and karyotype analysis and metaphase FISH of a chorionic villus sample, had all failed to reveal the duplication. The findings in this family add to the identification and delineation of a “critical region” for the DS phenotype on chromosome 21. Cryptic chromosomal abnormalities can be missed on a routine karyotype for investigation of abnormal prenatal ultrasound findings, lending support to the use of aCGH analysis in this setting.
doi:10.1136/jmg.2006.047373
PMCID: PMC2598003  PMID: 17237124
3.  aCGHViewer: A Generic Visualization Tool For aCGH data 
Cancer informatics  2006;2:36-43.
Array-Comparative Genomic Hybridization (aCGH) is a powerful high throughput technology for detecting chromosomal copy number aberrations (CNAs) in cancer, aiming at identifying related critical genes from the affected genomic regions. However, advancing from a dataset with thousands of tabular lines to a few candidate genes can be an onerous and time-consuming process. To expedite the aCGH data analysis process, we have developed a user-friendly aCGH data viewer (aCGHViewer) as a conduit between the aCGH data tables and a genome browser. The data from a given aCGH analysis are displayed in a genomic view comprised of individual chromosome panels which can be rapidly scanned for interesting features. A chromosome panel containing a feature of interest can be selected to launch a detail window for that single chromosome. Selecting a data point of interest in the detail window launches a query to the UCSC or NCBI genome browser to allow the user to explore the gene content in the chromosomal region. Additionally, aCGHViewer can display aCGH and expression array data concurrently to visually correlate the two. aCGHViewer is a stand alone Java visualization application that should be used in conjunction with separate statistical programs. It operates on all major computer platforms and is freely available at http://falcon.roswellpark.org/aCGHview/.
PMCID: PMC1847423  PMID: 17404607
array-CGH; CNA; gene expression; visualization
4.  aCGHViewer: A Generic Visualization Tool For aCGH data 
Cancer Informatics  2007;2:36-43.
Array-Comparative Genomic Hybridization (aCGH) is a powerful high throughput technology for detecting chromosomal copy number aberrations (CNAs) in cancer, aiming at identifying related critical genes from the affected genomic regions. However, advancing from a dataset with thousands of tabular lines to a few candidate genes can be an onerous and time-consuming process. To expedite the aCGH data analysis process, we have developed a user-friendly aCGH data viewer (aCGHViewer) as a conduit between the aCGH data tables and a genome browser. The data from a given aCGH analysis are displayed in a genomic view comprised of individual chromosome panels which can be rapidly scanned for interesting features. A chromosome panel containing a feature of interest can be selected to launch a detail window for that single chromosome. Selecting a data point of interest in the detail window launches a query to the UCSC or NCBI genome browser to allow the user to explore the gene content in the chromosomal region. Additionally, aCGHViewer can display aCGH and expression array data concurrently to visually correlate the two. aCGHViewer is a stand alone Java visualization application that should be used in conjunction with separate statistical programs. It operates on all major computer platforms and is freely available at http://falcon.roswellpark.org/aCGHview/.
PMCID: PMC1847423  PMID: 17404607
array-CGH; CNA; gene expression; visualization
5.  FOXO1 regulates expression of a microRNA cluster on X chromosome 
Aging (Albany NY)  2013;5(5):347-356.
Phosphoinositol-3-kinase (PI3K) pathway is a crucial modulator of many physiological and pathophysiological phenomena, including aging, diabetes and cancer. Protein kinase Akt, a downstream effector of PI3K, controls a plethora of cellular functions, including gene transcription. A key mechanism connecting Akt activity to changes in gene expression is inhibitory phosphorylation of FOXO family of transcription factors. Accordingly, altered expression of FOXO targets may account for many biological consequences of PI3K/Akt signaling. While the previous efforts focused on FOXO-dependent regulation of protein-coding genes, non-coding RNA genes have emerged as equally important targets of many transcription factors. Therefore, we utilized a regulated form of FOXO1 to profile FOXO1-dependent changes in miRNA expression in human cells. Both microarray hybridization and next-generation sequencing revealed changes in the products of a miRNA cluster on X chromosome. Rapid induction of these miRNAs occurred independently of de novo protein synthesis. Furthermore, inhibition of PI3K in cancer cell lines caused derepression of these miRNAs, as would be expected for FOXO-regulated genes. Members of the major oncogenic cascades are significantly overrepresented among the predicted targets of the miRNAs, consistent with tumor-suppressive role of FOXO1. The discovered miRNAs represent new candidate mediators of FOXO1 functions and possible biomarkers of its activity.
PMCID: PMC3701110  PMID: 23748164
the forkhead family of transcription factors; mir; miRNA; oncotarget; cancer
6.  Phase I Study of Arsenic Trioxide, High-Dose Cytarabine and Idarubicin to Down-Regulate Constitutive STAT3 Activity in <60 Year Old Acute Myeloid Leukemia Patients 
Cancer  2011;117(21):4831-4868.
Purpose
Constitutive activation of signal transducer and activator of transcription-3 (STAT3) was detected in blasts from approximately 50% of acute myeloid leukemia (AML) patients and was found to correlate with adverse outcome. In vitro treatment of AML blasts with arsenic trioxide (ATO) down-regulates STAT3 activity within six hours associated with a reduced viability within 48 hours.
Experimental Design
A phase I clinical trial to evaluate the biologically effective dose (BED) and/or the maximally tolerated dose (MTD) of ATO in vivo in conjunction with high-dose cytarabine (Hidac) and idarubicin (Ida) in AML patients <60 years old was conducted. Data were compared with historical 117 AML patients treated with Hidac/Ida.
Results
A total of 61 patients were enrolled onto 11 different dose levels (0.01 to 0.65 mg/kg ideal body weight). The MTD was 0.5 mg/kg. In comparison to historical controls, ATO/Hidac/Ida patients, while having similar pretreatment characteristics, had better overall survival (p=0.039).
Conclusions
ATO priming may have improved the outcome of <60 year old AML patients treated with Hidac/Ida. These data suggest that ATO might enhance the effect of chemotherapy. Further studies of this novel combination are warranted.
doi:10.1002/cncr.26097
PMCID: PMC3129468  PMID: 21456022
acute myeloid leukemia; signal transducer and activator of transcription 3; arsenic trioxide; treatment; phase I
7.  Molecular karyotypes of Hodgkin and Reed-Sternberg cells at disease onset reveal distinct copy number alterations in chemosensitive vs. refractory Hodgkin lymphoma 
Purpose
To determine the recurring DNA copy number alterations (CNAs) in classical Hodgkin lymphoma (HL) by microarray-based comparative genomic hybridization (aCGH) using laser capture micro-dissected CD30+ Hodgkin/Reed-Sternberg (HRS) cells.
Experimental Design
Archived tissues from 27 CD30+ HL plus control samples were analyzed by DNA microarrays. The HL molecular karyotypes were compared to the genomic profiles of germinal center B cells and treatment outcome (chemotherapy responsive vs. primary refractory disease).
Results
Gains and losses observed in >35% of HL samples were localized respectively to 22 and 12 chromosomal regions. Frequent gains (>65%) were associated with growth and proliferation, NF-κB activation, cell cycle control, apoptosis, and immune and lymphoid development. Frequent losses (>40%) observed encompassed tumor suppressor genes (SPRY1, NELL1, ID4), transcriptional repressors (TXNIP), SKP2 (ubiquitin ligase component) and an antagonist of NF-κB activation (PPARGC1A). In comparison to the germinal center profiles, the most frequent imbalances in HL were losses in 5p13 (AMACR, GDNF, SKP2), and gains in 7q36 (SHH) and 9q34 (ABL1, CDK9, LCN2, PTGES). Gains (>35%) in the HL chemoresponsive patients housed genes known to regulate T-cell trafficking or NF-κB activation (CCL22, CX3CL1, CCL17, DOK4 and IL10), whereas the refractory samples showed frequent loss of 4q27 (IL2/IL21), 17p12 and 19q13.3 gain (BCL3/RELB).
Conclusion
We identified non-random CNAs in the molecular karyotypes of classical HL. Several recurring genetic lesions correlated with disease outcome. These findings may be useful prognostic markers in the counseling and management of patients and for the development of novel therapeutic approaches in primary refractory HL.
doi:10.1158/1078-0432.CCR-10-1071
PMCID: PMC3096736  PMID: 21385932
8.  Upregulation of Hemoglobin Expression by Oxidative Stress in Hepatocytes and Its Implication in Nonalcoholic Steatohepatitis 
PLoS ONE  2011;6(9):e24363.
Recent studies revealed that hemoglobin is expressed in some non-erythrocytes and it suppresses oxidative stress when overexpressed. Oxidative stress plays a critical role in the pathogenesis of non-alcoholic steatohepatitis (NASH). This study was designed to investigate whether hemoglobin is expressed in hepatocytes and how it is related to oxidative stress in NASH patients. Analysis of microarray gene expression data revealed a significant increase in the expression of hemoglobin alpha (HBA1) and beta (HBB) in liver biopsies from NASH patients. Increased hemoglobin expression in NASH was validated by quantitative real time PCR. However, the expression of hematopoietic transcriptional factors and erythrocyte specific marker genes were not increased, indicating that increased hemoglobin expression in NASH was not from erythropoiesis, but could result from increased expression in hepatocytes. Immunofluorescence staining demonstrated positive HBA1 and HBB expression in the hepatocytes of NASH livers. Hemoglobin expression was also observed in human hepatocellular carcinoma HepG2 cell line. Furthermore, treatment with hydrogen peroxide, a known oxidative stress inducer, increased HBA1 and HBB expression in HepG2 and HEK293 cells. Importantly, hemoglobin overexpression suppressed oxidative stress in HepG2 cells. We concluded that hemoglobin is expressed by hepatocytes and oxidative stress upregulates its expression. Suppression of oxidative stress by hemoglobin could be a mechanism to protect hepatocytes from oxidative damage in NASH.
doi:10.1371/journal.pone.0024363
PMCID: PMC3171444  PMID: 21931690
9.  A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions 
Human Molecular Genetics  2010;19(14):2780-2791.
Down syndrome (DS) is caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is the most common genetic cause for developmental cognitive disability. The regions on Hsa21 are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this report, we describe a new mouse model for DS that carries duplications spanning the entire Hsa21 syntenic regions on all three mouse chromosomes. This mouse mutant exhibits DS-related neurological defects, including impaired cognitive behaviors, reduced hippocampal long-term potentiation and hydrocephalus. These results suggest that when all the mouse orthologs of the Hsa21 genes are triplicated, an abnormal cognitively relevant phenotype is the final outcome of the elevated expressions of these orthologs as well as all the possible functional interactions among themselves and/or with other mouse genes. Because of its desirable genotype and phenotype, this mutant may have the potential to serve as one of the reference models for further understanding the developmental cognitive disability associated with DS and may also be used for developing novel therapeutic interventions for this clinical manifestation of the disorder.
doi:10.1093/hmg/ddq179
PMCID: PMC2893810  PMID: 20442137
10.  Recurrent Deletion of 9q34 in Adult Normal Karyotype Precursor B Cell Acute Lymphoblastic Leukemia 
Cancer genetics and cytogenetics  2010;199(1):15-20.
The prognosis of adult normal karyotype (NK) precursor B cell acute lymphoblastic leukemia (B-ALL) has not improved over the last decade mainly because separation into distinct molecular subsets has been lacking and no targeted treatments are available. We screened the genome of blasts from ten adult NK B-ALL patients for novel genomic alterations by array comparative genomic hybridization and verified our results with fluorescent in situ hybridization and gene expression profile using the same probes. The results demonstrate cryptic deletions of 9q34 involving SET, PKN3, NUP188, ABL1 and NUP214 in three of the samples. The smallest deletion resulted in the likely juxtaposition of the SET and NUP214 genes. This aberration has not been described before in adult NK B-ALL. Larger number of samples is warranted to determine the prognostic significance of this cryptic deletion.
doi:10.1016/j.cancergencyto.2010.01.014
PMCID: PMC2862995  PMID: 20417863
11.  Role of Alcohol Metabolism in Non-Alcoholic Steatohepatitis 
PLoS ONE  2010;5(3):e9570.
Background
Non-alcoholic steatohepatitis (NASH) is a serious form of non-alcoholic fatty liver disease (NAFLD), associated with obesity and insulin resistance. Previous studies suggested that intestinal bacteria produced more alcohol in obese mice than lean animals.
Methodology/Principal Findings
To investigate whether alcohol is involved in the pathogenesis of NASH, the expression of inflammation, fibrosis and alcohol metabolism related genes in the liver tissues of NASH patients and normal controls (NCs) were examined by microarray (NASH, n = 7; NC, n = 4) and quantitative real-time PCR (NASH, n = 6; NC, n = 6). Genes related to liver inflammation and fibrosis were found to be elevated in NASH livers compared to normal livers. The most striking finding is the increased gene transcription of alcohol dehydrogenase (ADH) genes, genes for catalase and cytochrome P450 2E1, and aldehyde dehydrogenase genes. Immunoblot analysis confirmed the increased expression of ADH1 and ADH4 in NASH livers (NASH, n = 9; NC, n = 4).
Conclusions/Significance
The augmented activity of all the available genes of the pathways for alcohol catabolism suggest that 1) alcohol concentration was elevated in the circulation of NASH patients; 2) there was a high priority for the NASH livers to scavenge alcohol from the circulation. Our data is the first human evidence that suggests alcohol may contribute to the development of NAFLD.
doi:10.1371/journal.pone.0009570
PMCID: PMC2833196  PMID: 20221393
12.  Uniparentalism in Sporadic Colorectal Cancer is Independent of Imprint Status, and Coordinate for Chromosomes 14 and 18 
Cancer genetics and cytogenetics  2009;189(2):77-86.
Our previous allelotyping studies of 59 sporadic colorectal cancers revealed that loss of heterozygosity is most frequent for regions of chromosomes 14 and 18. Yet subsequent BAC microarray comparative genomic hybridization studies of the same tumor DNAs showed no corresponding pattern of copy number alteration for chromosome 14. To clarify this apparent discrepancy, we utilized hybridization to SNP microarrays; this revealed frequent uniparentalism for chromosome 14 and for chromosome 18. Based on the BAC array results combined with fluorescent in situ hybridization data, it was evident that uniparental disomy was occurring in many colorectal cancers as well as in additional chromosomes, and often coordinately involved chromosomes 14 and 18. Further studies examined the possibility that uniparentalism was directed towards the selection for imprinted genes, but no association with imprinting was observed.
doi:10.1016/j.cancergencyto.2008.10.011
PMCID: PMC2666006  PMID: 19215787
uniparental disomy; imprinting; genomic instability; colorectal cancer
13.  Targeted Deletion of p73 in Mice Reveals Its Role in T Cell Development and Lymphomagenesis 
PLoS ONE  2009;4(11):e7784.
Transcriptional silencing of the p73 gene through methylation has been demonstrated in human leukemias and lymphomas. However, the role of p73 in the malignant process remains to be explored. We show here that p73 acts as a T cell-specific tumor suppressor in a genetically defined mouse model, and that concomitant ablation of p53 and p73 predisposes mice to an increased incidence of thymic lymphomas compared to the loss of p53 alone. Our results demonstrate a causal role for loss of p73 in progression of T cell lymphomas to the stage of aggressive, disseminated disease. We provide evidence that tumorigenesis in mice lacking p53 and p73 proceeds through mechanisms involving altered patterns of gene expression, defects in early T cell development, impaired apoptosis, and the ensuing accumulation of chromosomal aberrations. Collectively, our data imply that tumor suppressive properties of p73 are highly dependent on cellular context, wherein p73 plays a major role in T cell development and neoplasia.
doi:10.1371/journal.pone.0007784
PMCID: PMC2771421  PMID: 19907659
14.  Microcephaly, sensorineural deafness and Currarino triad with duplication–deletion of distal 7q 
European Journal of Pediatrics  2009;169(4):475-481.
Currarino syndrome (CS) is a peculiar form of caudal regression syndrome [also known as autosomal dominant sacral agenesis (OMIM no. 176450)] characterised by (1) partial absence of the sacrum with intact first sacral vertebra, (2) a pre-sacral mass and (3) anorectal anomalies (Currarino triad). We studied a 3-year-old girl with Currarino triad who had additional systemic features and performed array comparative genomic hybridisation to look for chromosomal abnormalities. This girl had the typical spectrum of anomalies of the CS including (a) partial sacral agenesis (hemisacrum with remnants of only sacral S1–S2 vertebrae and a residual S3 vertebral body) associated with complete coccygeal agenesis, (b) pre-intrasacral dermoid, (c) intra-dural lipoma, (d) ectopic anus and (e) tethered cord. She had, in addition, pre- and post-natal growth impairment (<3rd percentile), severe microcephaly (<−3 SD) with normal gyration pattern and lack of cortical thickening associated with a hypoplastic inferior vermis, facial dysmorphism, sensorineural deafness and decreased serum levels of IGF-1. A de novo 10.3-Mb duplication of 7q34–q35 and an 8.8-Mb deletion on 7q36 were identified in this patient. The Homeobox HLXB9 (CS) gene is contained within the deletion accounting for the CS phenotype including microcephaly. The spectrums of associated abnormalities in the IGF-1 deficiency growth retardation with sensorineural deafness and mental retardation syndrome (OMIM no. 608747) are discussed. To the best of our knowledge, this is the first reported case of a patient with distal 7q chromosomal imbalance and features of CS triad (including microcephaly) and the first documented case of a patient with normal gyration pattern microcephaly. The spectrum of associated anomalies in this newly recognised phenotype complex consists of growth failure, typical facial anomalies with additional (previously unreported) nervous system abnormalities (e.g. sensorineural deafness) and somatomedin C deficiency.
doi:10.1007/s00431-009-1061-6
PMCID: PMC2820683  PMID: 19838731
Caudal regression syndrome; Absence of sacrum; Pre-sacral mass; Anorectal anomalies; Microcephaly; Sensorineural deafness; IGF-1 deficiency
15.  A de novo 1p34.2 microdeletion identifies the synaptic vesicle gene RIMS3 as a novel candidate for autism 
Journal of Medical Genetics  2009;47(2):81-90.
Background
A child with autism and mild microcephaly was found to have a de novo 3.3 Mb microdeletion on chromosome 1p34.2p34.3. The hypothesis is tested that this microdeletion contains one or more genes that underlie the autism phenotype in this child and in other children with autism spectrum disorders.
Methods
To search for submicroscopic chromosomal rearrangements in the child, array comparative genomic hybridisation (aCGH) was performed using a 19 K whole genome human bacterial artificial chromosome (BAC) array and the Illumina 610-Quad BeadChip microarray. Ingenuity pathway analysis (IPA) was used to construct functional biological networks to identify candidate autism genes. To identify putative functional variants in candidate genes, mutation screening was performed using polymerase chain reaction (PCR) based Sanger sequencing in 512 unrelated autism patients and 462 control subjects.
Results
A de novo 3.3 Mb deletion containing ∼43 genes in chromosome 1p34.2p34.3 was identified and subsequently confirmed using fluorescence in situ hybridization (FISH). Literature review and bioinformatics analyses identified Regulating Synaptic Membrane Exocytosis 3 (RIMS3) as the most promising autism candidate gene. Mutation screening of this gene in autism patients identified five inherited coding variants, including one (p.E177A) that segregated with the autism phenotype in a sibship, was predicted to be deleterious, and was absent in 1161 controls.
Conclusions
This case report and mutation screening data suggest that RIMS3 is an autism causative or contributory gene. Functional studies of RIMS3 variants such as p.E177A should provide additional insight into the role of synaptic proteins in the pathophysiology of autism.
doi:10.1136/jmg.2008.065821
PMCID: PMC2921284  PMID: 19546099
autism; microcephaly; mental retardation; copy number variants; synapse; molecular genetics; neurosciences; psychiatry
16.  Two Functional Coding Single Nucleotide Polymorphisms in STK15 (Aurora-A) Coordinately Increase Esophageal Cancer Risk 
Cancer research  2005;65(9):3548-3554.
STK15/Aurora-A is a serine/threonine kinase essential for chromosome segregation and cytokinesis, and is considered to be a cancer susceptibility gene in mice and humans. Two coding single nucleotide polymorphisms in Aurora-A, 91T>A [phenylalanine/isoleucine (F/I)] and 169G>A [valine/isoleucine (V/I)], create four haplotypes, 91T-169G, 91A-169G, 91T-169A, and 91A-169A. We evaluated the association between these coding single nucleotide polymorphisms and esophageal cancer risk by genotyping 197 esophageal cancer cases and 146 controls. Haplotype 91A-169A (I31/I57) was observed to be statistically more frequent in cancer cases (odds ratio, 3.1452; 95% confidence interval, 1.0258–9.6435). Functional differences among the four isoforms were then analyzed to reveal the source of the cancer risk. Kinase activity levels of I31/I57 and F31/I57 were reduced to 15% and 40% compared with I31/V57 in vivo and in vitro. We considered the differences between the kinase activities and divided individuals into four categories of Aurora-A haplotype combination. Category I had 57.5% or less kinase activity compared with the most common category, category III, and had a significantly higher estimated cancer risk (odds ratio, 5.5328; 95% confidence interval, 1.8149–16.8671). Abnormal nuclear morphology, a characteristic of genomic instability, was observed to be 30 to 40 times more frequent in human immortalized fibroblast cells over-expressing I31/I57 or F31/I57 compared with the others. Furthermore, significantly higher levels of chromosomal instability were observed in cancers in category I (homozygote 91T-169A) than those in category III (homozygous 91A-169G). These results indicate that the less kinase active Aurora-A haplotype combinations might induce genomic instability and increase esophageal cancer risk either in a recessive or a dominant manner.
doi:10.1158/0008-5472.CAN-04-2149
PMCID: PMC2536656  PMID: 15867347
17.  Novel Submicroscopic chromosomal abnormalities detected in Autism Spectrum Disorder 
Biological psychiatry  2008;63(12):1111-1117.
Background
One genetic mechanism known to be associated with autism spectrum disorders (ASD) is chromosomal abnormalities. The identification of copy number variants (CNV) i.e. microdeletions and microduplications that are undetectable at the level of traditional cytogenetic analysis allows the potential association of submicroscopic chromosomal imbalances and human disease.
Methods
We performed array comparative genomic hybridization (aCGH) utilizing a 19K whole genome tiling path bacterial artificial chromosome (BAC) microarray on 397 unrelated subjects with autism spectrum disorder (ASD). Common CNV were excluded using a control group comprised of 372 individuals from the NIMH Genetics Initiative Control samples. Confirmation studies were performed on all remaining CNV using FISH (Fluorescence In Situ Hybridization), microsatellite analysis and/or quantitative PCR analysis.
Results
A total of 51 CNV were confirmed in 46 ASD subjects. Three maternal interstitial duplications of 15q11-q13 known to be associated with ASD were identified. The other 48 CNV ranged in size from 189 kb to 5.5 Mb and contained from 0 to ~40 RefSeq genes. Seven CNV were de novo and 44 were inherited.
Conclusions
51 autism-specific CNV were identified in 46/397 ASD patients using a 19K BAC microarray for an overall rate of 11.6%. These microdeletions and microduplications cause gene dosage imbalance in 272 genes many of which could be considered as candidate genes for autism.
doi:10.1016/j.biopsych.2008.01.009
PMCID: PMC2440346  PMID: 18374305
autism; array comparative genomic hybridization; microdeletions; microduplications
18.  aCGH Local Copy Number Aberrations Associated with Overall Copy Number Genomic Instability in Colorectal Cancer: Coordinate Involvement of the Regions Including BCR and ABL 
Mutation research  2007;615(1-2):1-11.
In order to identify small regions of the genome whose specific copy number alteration is associated with high genomic instability in the form of overall genome-wide copy number aberrations, we have analyzed array-based comparative genomic hybridization (aCGH) data from 33 sporadic colorectal carcinomas. Copy number changes of a small number of specific regions were significantly correlated with elevated overall amplifications and deletions scattered throughout the entire genome. One significant region at 9q34 includes the c-ABL gene Another region spanning 22q11–13 includes the breakpoint cluster region (BCR) of the Philadelphia chromosome Coordinate 22q11–13 alterations were observed in nine of eleven tumors with the 9q34 alteration Additional regions on 1q and 14q were associated with overall genome-wide copy number changes, while copy number aberrations on chromosome 7p, 7q, and 13q21.1–31.3 were found associated with this instability only in tumors from patients with a smoking history Our analysis demonstrates there are a small number of regions of the genome where gain or loss is commonly associated with a tumor’s overall level of copy number aberrations Our finding BCR and ABL located within two of the instability-associated regions, and the involvement of these two regions occurring coordinately, suggests a system akin to the BCR-ABL translocation of CML may be involved in genomic instability in about one-third of human colorectal carcinomas.
doi:10.1016/j.mrfmmm.2006.09.006
PMCID: PMC1866266  PMID: 17196995
genomic instability; colorectal cancer; array-based CGH
19.  Gene-resolution analysis of DNA copy number variation using oligonucleotide expression microarrays 
BMC Genomics  2007;8:111.
Background
Array-based comparative genomic hybridization (aCGH) is a high-throughput method for measuring genome-wide DNA copy number changes. Current aCGH methods have limited resolution, sensitivity and reproducibility. Microarrays for aCGH are available only for a few organisms and combination of aCGH data with expression data is cumbersome.
Results
We present a novel method of using commercial oligonucleotide expression microarrays for aCGH, enabling DNA copy number measurements and expression profiles to be combined using the same platform. This method yields aCGH data from genomic DNA without complexity reduction at a median resolution of approximately 17,500 base pairs. Due to the well-defined nature of oligonucleotide probes, DNA amplification and deletion can be defined at the level of individual genes and can easily be combined with gene expression data.
Conclusion
A novel method of gene resolution analysis of copy number variation (graCNV) yields high-resolution maps of DNA copy number changes and is applicable to a broad range of organisms for which commercial oligonucleotide expression microarrays are available. Due to the standardization of oligonucleotide microarrays, graCNV results can reliably be compared between laboratories and can easily be combined with gene expression data using the same platform.
doi:10.1186/1471-2164-8-111
PMCID: PMC1868757  PMID: 17470268
20.  Genetic analysis of Down syndrome-associated heart defects in mice 
Human Genetics  2011;130(5):623-632.
Human trisomy 21, the chromosomal basis of Down syndrome (DS), is the most common genetic cause of heart defects. Regions on human chromosome 21 (Has21) are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this study, we have analyzed the impact of duplications of each syntenic region on cardiovascular development in mice and have found that only the duplication on Mmu16, i.e., Dp(16)1Yey, is associated with heart defects. Furthermore, we generated two novel mouse models carrying a 5.43-Mb duplication and a reciprocal deletion between Tiam1 and Kcnj6 using chromosome engineering, Dp(Tiam1-Kcnj6)Yey/+ and Df(Tiam1-Kcnj6)Yey/+, respectively, within the 22.9-Mb syntenic region on Mmu16. We found that Dp(Tiam1-Kcnj6)Yey/+, but not Dp(16)1Yey/Df(Tiam1-Kcnj6)Yey, resulted in heart defects, indicating that triplication of the Tiam1-Knj6 region is necessary and sufficient to cause DS-associated heart defects. Our transcriptional analysis of Dp(Tiam1-Kcnj6)Yey/+ embryos confirmed elevated expression levels for the genes located in the Tiam-Kcnj6 region. Therefore, we established the smallest critical genomic region for DS-associated heart defects to lay the foundation for identifying the causative gene(s) for this phenotype.
doi:10.1007/s00439-011-0980-2
PMCID: PMC3257027  PMID: 21442329
Down syndrome; trisomy 21; congenital heart defects; mouse models for human genetic disease; chromosome engineering; genetic analysis
21.  Common Genetic Variants Are Associated with Accelerated Bone Mineral Density Loss after Hematopoietic Cell Transplantation 
PLoS ONE  2011;6(10):e25940.
Background
Bone mineral density (BMD) loss commonly occurs after hematopoietic cell transplantation (HCT). Hypothesizing that genetic variants may influence post-HCT BMD loss, we conducted a prospective study to examine the associations of single nucleotide polymorphisms (SNP) in bone metabolism pathways and acute BMD loss after HCT.
Methods and Findings
We genotyped 122 SNPs in 45 genes in bone metabolism pathways among 121 autologous and allogeneic HCT patients. BMD changes from pre-HCT to day +100 post-HCT were analyzed in relation to these SNPs in linear regression models. After controlling for clinical risk factors, we identified 16 SNPs associated with spinal or femoral BMD loss following HCT, three of which have been previously implicated in genome-wide association studies of bone phenotypes, including rs2075555 in COL1A1, rs9594738 in RANKL, and rs4870044 in ESR1. When multiple SNPs were considered simultaneously, they explained 5–35% of the variance in post-HCT BMD loss. There was a significant trend between the number of risk alleles and the magnitude of BMD loss, with patients carrying the most risk alleles having the greatest loss.
Conclusion
Our data provide the first evidence that common genetic variants play an important role in BMD loss among HCT patients similar to age-related BMD loss in the general population. This infers that the mechanism for post-HCT bone loss is a normal aging process that is accelerated during HCT. A limitation of our study comes from its small patient population; hence future larger studies are warranted to validate our findings.
doi:10.1371/journal.pone.0025940
PMCID: PMC3195081  PMID: 22022476
22.  Familial 4.3 Mb duplication of 21q22 sheds new light on the Down syndrome critical region 
BMJ Case Reports  2009;2009:bcr05.2009.1914.
A 4.3 Mb duplication of chromosome 21 bands q22.13–q22.2 was diagnosed by interphase fluorescent in situ hybridisation (FISH) in a 31 week gestational age baby with cystic hygroma and hydrops; the duplication was later found in the mother and in her 8-year-old daughter. All had the facial gestalt of Down syndrome (DS). This is the smallest accurately defined duplication of chromosome 21 reported with a DS phenotype. The duplication encompasses the gene DYRK1 but not DSCR1 or DSCAM. Previous karyotype analysis and telomere screening of the mother, and karyotype analysis and metaphase FISH of a chorionic villus sample, had all failed to reveal the duplication. The findings in this family add to the identification and delineation of a “critical region” for the DS phenotype on chromosome 21.
doi:10.1136/bcr.05.2009.1914
PMCID: PMC3027932  PMID: 21686961

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