Publications by authors named "Sau W Cheung"

33 Publications

Cytogenetically visible inversions are formed by multiple molecular mechanisms.

Hum Mutat 2020 11 1;41(11):1979-1998. Epub 2020 Oct 1.

Department of Molecular Medicine and Surgery, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.

Cytogenetically detected inversions are generally assumed to be copy number and phenotypically neutral events. While nonallelic homologous recombination is thought to play a major role, recent data suggest the involvement of other molecular mechanisms in inversion formation. Using a combination of short-read whole-genome sequencing (WGS), 10X Genomics Chromium WGS, droplet digital polymerase chain reaction and array comparative genomic hybridization we investigated the genomic structure of 18 large unique cytogenetically detected chromosomal inversions and achieved nucleotide resolution of at least one chromosomal inversion junction for 13/18 (72%). Surprisingly, we observed that seemingly copy number neutral inversions can be accompanied by a copy-number gain of up to 350 kb and local genomic complexities (3/18, 17%). In the resolved inversions, the mutational signatures are consistent with nonhomologous end-joining (8/13, 62%) or microhomology-mediated break-induced replication (5/13, 38%). Our study indicates that short-read 30x coverage WGS can detect a substantial fraction of chromosomal inversions. Moreover, replication-based mechanisms are responsible for approximately 38% of those events leading to a significant proportion of inversions that are actually accompanied by additional copy-number variation potentially contributing to the overall phenotypic presentation of those patients.
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http://dx.doi.org/10.1002/humu.24106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702065PMC
November 2020

Correction: A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

Genet Med 2019 Sep;21(9):2159-2160

Department of Pediatrics, Université de Montréal, Montreal, QC, Canada.

The original version of this Article contained an error in the spelling of the author Siddharth Banka, which was incorrectly given as Siddhart Banka. This has now been corrected in both the PDF and HTML versions of the Article.
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http://dx.doi.org/10.1038/s41436-018-0413-xDOI Listing
September 2019

A new microdeletion syndrome involving TBC1D24, ATP6V0C, and PDPK1 causes epilepsy, microcephaly, and developmental delay.

Genet Med 2019 05 24;21(5):1058-1064. Epub 2018 Sep 24.

Department of Pediatrics, Université de Montréal, Montreal, QC, Canada.

Purpose: Contiguous gene deletions are known to cause several neurodevelopmental syndromes, many of which are caused by recurrent events on chromosome 16. However, chromosomal microarray studies (CMA) still yield copy-number variants (CNVs) of unknown clinical significance. We sought to characterize eight individuals with overlapping 205-kb to 504-kb 16p13.3 microdeletions that are distinct from previously published deletion syndromes.

Methods: Clinical information on the patients and bioinformatic scores for the deleted genes were analyzed.

Results: All individuals in our cohort displayed developmental delay, intellectual disability, and various forms of seizures. Six individuals were microcephalic and two had strabismus. The deletion was absent in all 13 parents who were available for testing. The area of overlap encompasses seven genes including TBC1D24, ATP6V0C, and PDPK1 (also known as PDK1). Bi-allelic TBC1D24 pathogenic variants are known to cause nonsyndromic deafness, epileptic disorders, or DOORS syndrome (deafness, onychodystrophy, osteodystrophy, mental retardation, seizures). Sanger sequencing of the nondeleted TBC1D24 allele did not yield any additional pathogenic variants.

Conclusions: We propose that 16p13.3 microdeletions resulting in simultaneous haploinsufficiencies of TBC1D24, ATP6V0C, and PDPK1 cause a novel rare contiguous gene deletion syndrome of microcephaly, developmental delay, intellectual disability, and epilepsy.
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http://dx.doi.org/10.1038/s41436-018-0290-3DOI Listing
May 2019

Microarray analysis: First-trimester maternal serum free β-hCG and the risk of significant copy number variants.

Prenat Diagn 2018 11 21;38(12):971-978. Epub 2018 Sep 21.

Division of Maternal-Fetal Medicine, Department of Obstetrics & Gynecology, Lenox Hill Hospital, Northwell Health, New York City, New York.

Objective: To determine whether abnormal levels of first-trimester maternal serum free β-hCG and PAPP-A are associated with significant copy number variants (CNVs) on chromosomal microarray analysis (CMA).

Methods: Retrospective cohort of singleton prenatal CMA studies (n = 2880). Cases with an abnormal karyotype, benign familial or de novo variants, and absence of heterozygosity were excluded. The prevalence of abnormal serum analytes was compared between patients with significant CNVs (n = 56) and those with normal CMA (n = 884). Odds ratios (ORs) and 95% confidence intervals (CI) were calculated using Fisher's exact test. Mantel-Haenszel method was utilized to adjust ORs for prenatal diagnostic procedure type and indications for testing. Statistical significance was determined as P value < 0.05.

Results: Abnormally low serum free β-hCG (≤0.45 MoM) was associated with an increased risk of significant CNVs (OR 3.53, 95% CI, 1.25-8.66, P < 0.01). This association remained significant after adjusting for abnormal nuchal translucency and advanced maternal age (AMA) (adjusted OR 3.04, 95% CI, 1.05-7.48, P < 0.05) or procedure type and AMA (adjusted OR 3.21, 95% CI 1.13-8.16, P < 0.05). The associations of abnormally high serum free β-hCG, low PAPP-A, and high PAPP-A with significant CNVs were not statistically significant.

Conclusion: Low first-trimester serum β-hCG is associated with an increased risk of significant CNVs on CMA.
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http://dx.doi.org/10.1002/pd.5350DOI Listing
November 2018

Novel applications of array comparative genomic hybridization in molecular diagnostics.

Expert Rev Mol Diagn 2018 06 31;18(6):531-542. Epub 2018 May 31.

a Department of Molecular and Human Genetics , Baylor College of Medicine , Houston , TX , USA.

Introduction: In 2004, the implementation of array comparative genomic hybridization (array comparative genome hybridization [CGH]) into clinical practice marked a new milestone for genetic diagnosis. Array CGH and single-nucleotide polymorphism (SNP) arrays enable genome-wide detection of copy number changes in a high resolution, and therefore microarray has been recognized as the first-tier test for patients with intellectual disability or multiple congenital anomalies, and has also been applied prenatally for detection of clinically relevant copy number variations in the fetus. Area covered: In this review, the authors summarize the evolution of array CGH technology from their diagnostic laboratory, highlighting exonic SNP arrays developed in the past decade which detect small intragenic copy number changes as well as large DNA segments for the region of heterozygosity. The applications of array CGH to human diseases with different modes of inheritance with the emphasis on autosomal recessive disorders are discussed. Expert commentary: An exonic array is a powerful and most efficient clinical tool in detecting genome wide small copy number variants in both dominant and recessive disorders. However, whole-genome sequencing may become the single integrated platform for detection of copy number changes, single-nucleotide changes as well as balanced chromosomal rearrangements in the near future.
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http://dx.doi.org/10.1080/14737159.2018.1479253DOI Listing
June 2018

Universal Prenatal Chromosomal Microarray Analysis: Additive Value and Clinical Dilemmas in Fetuses with a Normal Karyotype.

Am J Perinatol 2017 03 17;34(4):340-348. Epub 2016 Aug 17.

Maternal-Fetal Medicine, Department of Obstetrics and Gynecology, Lenox-Hill Hospital, New York, New York.

 To assess the additive value of prenatal chromosomal microarray analysis (CMA) for all indications and the likelihood of detecting pathologic copy number variations (CNVs) based on specific indications.  A retrospective analysis was performed on amniocentesis and chorionic villi sampling results obtained between 2010 and 2014 in a single institution. A total of 3,314 consecutive patients undergoing invasive genetic testing for different indications were offered CMA in addition to standard karyotype. The prevalence of pathologic CNVs was compared between patients with low-risk indications and those with high-risk indications. Likewise, the prevalence of pathologic CNVs among patients with different sonographic abnormalities was calculated and compared with the low-risk group. Chi-square and Fisher exact tests were used for statistical analysis.  The prevalence of pathologic CNVs was significantly higher in patients with high-risk indications and specifically those with sonographic abnormalities, compared with the low-risk group (2.8 and 5.9% vs. 0.4%, respectively; all  < 0.05).  Prenatal CMA detected clinically relevant CNVs in fetuses with a normal karyotype. Major structural malformations and nuchal translucency (NT) ≥ 3.0 mm are associated with the highest risk for a CMA abnormality. Nevertheless, the prevalence of pathologic CNVs in the low-risk population was high enough (1:250) to consider genetic counseling in this group.
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http://dx.doi.org/10.1055/s-0036-1586501DOI Listing
March 2017

Application of DNA Microarray to Clinical Diagnostics.

Methods Mol Biol 2016 ;1368:111-32

Medical Genetics Laboratories, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.

Microarray-based technology to conduct array comparative genomic hybridization (aCGH) has made a significant impact on the diagnosis of human genetic diseases. Such diagnoses, previously undetectable by traditional G-banding chromosome analysis, are now achieved by identifying genomic copy number variants (CNVs) using the microarray. Not only can hundreds of well-characterized genetic syndromes be detected in a single assay, but new genomic disorders and disease-causing genes can also be discovered through the utilization of aCGH technology. Although other platforms such as single nucleotide polymorphism (SNP) arrays can be used for detecting CNVs, in this chapter we focus on describing the methods for performing aCGH using Agilent oligonucleotide arrays for both prenatal (e.g., amniotic fluid and chorionic villus sample) and postnatal samples (e.g., blood).
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http://dx.doi.org/10.1007/978-1-4939-3136-1_9DOI Listing
September 2016

Copy number variants in patients with intellectual disability affect the regulation of ARX transcription factor gene.

Hum Genet 2015 Nov 4;134(11-12):1163-82. Epub 2015 Sep 4.

Department of Physiology, Brain and Mind Research Institute, Sydney Medical School, University of Sydney, 94 Mallet Street, Camperdown, NSW, 2050, Australia.

Protein-coding mutations in the transcription factor-encoding gene ARX cause various forms of intellectual disability (ID) and epilepsy. In contrast, variations in surrounding non-coding sequences are correlated with milder forms of non-syndromic ID and autism and had suggested the importance of ARX gene regulation in the etiology of these disorders. We compile data on several novel and some already identified patients with or without ID that carry duplications of ARX genomic region and consider likely genetic mechanisms underlying the neurodevelopmental defects. We establish the long-range regulatory domain of ARX and identify its brain region-specific autoregulation. We conclude that neurodevelopmental disturbances in the patients may not simply arise from increased dosage due to ARX duplication. This is further exemplified by a small duplication involving a non-functional ARX copy, but with duplicated enhancers. ARX enhancers are located within a 504-kb region and regulate expression specifically in the forebrain in developing and adult zebrafish. Transgenic enhancer-reporter lines were used as in vivo tools to delineate a brain region-specific negative and positive autoregulation of ARX. We find autorepression of ARX in the telencephalon and autoactivation in the ventral thalamus. Fluorescently labeled brain regions in the transgenic lines facilitated the identification of neuronal outgrowth and pathfinding disturbances in the ventral thalamus and telencephalon that occur when arxa dosage is diminished. In summary, we have established a model for how breakpoints in long-range gene regulation alter the expression levels of a target gene brain region-specifically, and how this can cause subtle neuronal phenotypes relating to the etiology of associated neuropsychiatric disease.
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http://dx.doi.org/10.1007/s00439-015-1594-xDOI Listing
November 2015

NUDT21-spanning CNVs lead to neuropsychiatric disease and altered MeCP2 abundance via alternative polyadenylation.

Elife 2015 Aug 27;4. Epub 2015 Aug 27.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.

The brain is sensitive to the dose of MeCP2 such that small fluctuations in protein quantity lead to neuropsychiatric disease. Despite the importance of MeCP2 levels to brain function, little is known about its regulation. In this study, we report eleven individuals with neuropsychiatric disease and copy-number variations spanning NUDT21, which encodes a subunit of pre-mRNA cleavage factor Im. Investigations of MECP2 mRNA and protein abundance in patient-derived lymphoblastoid cells from one NUDT21 deletion and three duplication cases show that NUDT21 regulates MeCP2 protein quantity. Elevated NUDT21 increases usage of the distal polyadenylation site in the MECP2 3' UTR, resulting in an enrichment of inefficiently translated long mRNA isoforms. Furthermore, normalization of NUDT21 via siRNA-mediated knockdown in duplication patient lymphoblasts restores MeCP2 to normal levels. Ultimately, we identify NUDT21 as a novel candidate for intellectual disability and neuropsychiatric disease, and elucidate a mechanism of pathogenesis by MeCP2 dysregulation via altered alternative polyadenylation.
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http://dx.doi.org/10.7554/eLife.10782DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4586391PMC
August 2015

Accurate description of DNA-based noninvasive prenatal screening.

N Engl J Med 2015 Apr 1;372(17):1675-7. Epub 2015 Apr 1.

Baylor College of Medicine, Houston, TX.

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http://dx.doi.org/10.1056/NEJMc1412222DOI Listing
April 2015

Genitourinary defects associated with genomic deletions in 2p15 encompassing OTX1.

PLoS One 2014 9;9(9):e107028. Epub 2014 Sep 9.

Center for Reproductive Medicine, Baylor College of Medicine, Houston, Texas, United States of America; Scott Department of Urology, Baylor College of Medicine, Houston, Texas, United States of America; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.

Normal development of the genitourinary (GU) tract is a complex process that frequently goes awry. In male children the most frequent congenital GU anomalies are cryptorchidism (1-4%), hypospadias (1%) and micropenis (0.35%). Bladder exstrophy and epispadias complex (BEEC) (1∶47000) occurs less frequently but significantly impacts patients' lives. Array comparative genomic hybridization (aCGH) identified seven individuals with overlapping deletions in the 2p15 region (66.0 kb-5.6 Mb). Six of these patients have GU defects, while the remaining patient has no GU defect. These deletions encompass the transcription factor OTX1. Subjects 2-7 had large de novo CNVs (2.39-6.31 Mb) and exhibited features similar to those associated with the 2p15p16.1 and 2p15p14 microdeletion syndromes, including developmental delay, short stature, and variable GU defects. Subject-1 with BEEC had the smallest deletion (66 kb), which deleted only one copy of OTX1. Otx1-null mice have seizures, prepubescent transient growth retardation and gonadal defects. Two subjects have short stature, two have seizures, and six have GU defects, mainly affecting the external genitalia. The presence of GU defects in six patients in our cohort and eight of thirteen patients reported with deletions within 2p14p16.1 (two with deletion of OTX1) suggest that genes in 2p15 are important for GU development. Genitalia defects in these patients could result from the effect of OTX1 on pituitary hormone secretion or on the regulation of SHH signaling, which is crucial for development of the bladder and genitalia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0107028PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159299PMC
May 2015

Genetic diagnosis of autism spectrum disorders: the opportunity and challenge in the genomics era.

Crit Rev Clin Lab Sci 2014 Oct 30;51(5):249-62. Epub 2014 May 30.

Department of Pediatrics and Neurobiology, Duke University School of Medicine , Durham, NC , USA .

A genetic etiology for autism spectrum disorders (ASDs) was first suggested from twin studies reported in the 1970s. The identification of gene mutations in syndromic ASDs provided evidence to support a genetic cause of ASDs. More recently, genome-wide copy number variant and sequence analyses have uncovered a list of rare and highly penetrant copy number variants (CNVs) or single nucleotide variants (SNVs) associated with ASDs, which has strengthened the claim of a genetic etiology for ASDs. Findings from research studies in the genetics of ASD now support an important role for molecular diagnostics in the clinical genetics evaluation of ASDs. Various molecular diagnostic assays including single gene tests, targeted multiple gene panels and copy number analysis should all be considered in the clinical genetics evaluation of ASDs. Whole exome sequencing could also be considered in selected clinical cases. However, the challenge that remains is to determine the causal role of genetic variants identified through molecular testing. Variable expressivity, pleiotropic effects and incomplete penetrance associated with CNVs and SNVs also present significant challenges for genetic counseling and prenatal diagnosis.
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http://dx.doi.org/10.3109/10408363.2014.910747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937018PMC
October 2014

Delineation of candidate genes responsible for structural brain abnormalities in patients with terminal deletions of chromosome 6q27.

Eur J Hum Genet 2015 Jan 16;23(1):54-60. Epub 2014 Apr 16.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Patients with terminal deletions of chromosome 6q present with structural brain abnormalities including agenesis of corpus callosum, hydrocephalus, periventricular nodular heterotopia, and cerebellar malformations. The 6q27 region harbors genes that are important for the normal development of brain and delineation of a critical deletion region for structural brain abnormalities may lead to a better genotype-phenotype correlation. We conducted a detailed clinical and molecular characterization of seven unrelated patients with deletions involving chromosome 6q27. All patients had structural brain abnormalities. Using array comparative genomic hybridization, we mapped the size, extent, and genomic content of these deletions. The smallest region of overlap spans 1.7 Mb and contains DLL1, THBS2, PHF10, and C6orf70 (ERMARD) that are plausible candidates for the causation of structural brain abnormalities. Our study reiterates the importance of 6q27 region in normal development of brain and helps identify putative genes in causation of structural brain anomalies.
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http://dx.doi.org/10.1038/ejhg.2014.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4266737PMC
January 2015

Expanding the genotype-phenotype correlation in subtelomeric 19p13.3 microdeletions using high resolution clinical chromosomal microarray analysis.

Am J Med Genet A 2013 Dec 2;161A(12):2953-63. Epub 2013 Oct 2.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas; Department of Pediatrics-Hematology-Oncology, Baylor College of Medicine and Texas Children's Cancer Center, Houston, Texas.

Structural rearrangements of chromosome 19p are rare, and their resulting phenotypic consequences are not well defined. This is the first study to report a cohort of eight patients with subtelomeric 19p13.3 microdeletions, identified using clinical chromosomal microarray analysis (CMA). The deletion sizes ranged from 0.1 to 0.86 Mb. Detailed analysis of the patients' clinical features has enabled us to define a constellation of clinical abnormalities that include growth delay, multiple congenital anomalies, global developmental delay, learning difficulties, and dysmorphic facial features. There are eight genes in the 19p13.3 region that may potentially contribute to the clinical phenotype via haploinsufficiency. Moreover, in silico genomic analysis of 19p13.3 microdeletion breakpoints revealed numerous highly repetitive sequences, suggesting LINEs/SINEs-mediated events in generating these microdeletions. Thus, subtelomeric 19p13.3 appears important for normal embryonic and childhood development. The clinical description of patients with deletions in this genomic interval will assist clinicians to identify and treat individuals with similar deletions.
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http://dx.doi.org/10.1002/ajmg.a.35886DOI Listing
December 2013

TM4SF20 ancestral deletion and susceptibility to a pediatric disorder of early language delay and cerebral white matter hyperintensities.

Am J Hum Genet 2013 Aug 27;93(2):197-210. Epub 2013 Jun 27.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

White matter hyperintensities (WMHs) of the brain are important markers of aging and small-vessel disease. WMHs are rare in healthy children and, when observed, often occur with comorbid neuroinflammatory or vasculitic processes. Here, we describe a complex 4 kb deletion in 2q36.3 that segregates with early childhood communication disorders and WMH in 15 unrelated families predominantly from Southeast Asia. The premature brain aging phenotype with punctate and multifocal WMHs was observed in ~70% of young carrier parents who underwent brain MRI. The complex deletion removes the penultimate exon 3 of TM4SF20, a gene encoding a transmembrane protein of unknown function. Minigene analysis showed that the resultant net loss of an exon introduces a premature stop codon, which, in turn, leads to the generation of a stable protein that fails to target to the plasma membrane and accumulates in the cytoplasm. Finally, we report this deletion to be enriched in individuals of Vietnamese Kinh descent, with an allele frequency of about 1%, embedded in an ancestral haplotype. Our data point to a constellation of early language delay and WMH phenotypes, driven by a likely toxic mechanism of TM4SF20 truncation, and highlight the importance of understanding and managing population-specific low-frequency pathogenic alleles.
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http://dx.doi.org/10.1016/j.ajhg.2013.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3738832PMC
August 2013

MCTP2 is a dosage-sensitive gene required for cardiac outflow tract development.

Hum Mol Genet 2013 Nov 16;22(21):4339-48. Epub 2013 Jun 16.

Department of Molecular and Human Genetics.

Coarctation of the aorta (CoA) and hypoplastic left heart syndrome (HLHS) have been reported in rare individuals with large terminal deletions of chromosome 15q26. However, no single gene important for left ventricular outflow tract (LVOT) development has been identified in this region. Using array-comparative genomic hybridization, we identified two half-siblings with CoA with a 2.2 Mb deletion on 15q26.2, inherited from their mother, who was mosaic for this deletion. This interval contains an evolutionary conserved, protein-coding gene, MCTP2 (multiple C2-domains with two transmembrane regions 2). Using gene-specific array screening in 146 individuals with non-syndromic LVOT obstructive defects, another individual with HLHS and CoA was found to have a de novo 41 kb intragenic duplication within MCTP2, predicted to result in premature truncation, p.F697X. Alteration of Mctp2 gene expression in Xenopus laevis embryos by morpholino knockdown and mRNA overexpression resulted in the failure of proper OT development, confirming the functional importance of this dosage-sensitive gene for cardiogenesis. Our results identify MCTP2 as a novel genetic cause of CoA and related cardiac malformations.
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http://dx.doi.org/10.1093/hmg/ddt283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3792692PMC
November 2013

A mosaic 2q24.2 deletion narrows the critical region to a 0.4 Mb interval that includes TBR1, TANK, and PSMD14.

Am J Med Genet A 2013 Apr 26;161A(4):841-4. Epub 2013 Feb 26.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Interstitial deletions involving 2q24 have been associated with a wide range of phenotypes including intellectual disability and short stature. To date, the smallest common region among reported cases of deletions in this region is approximately 2.65 Mb and contains 15 genes. In the present case report, we describe an 18-year-old male with mild intellectual disability, short stature, and mosaicism for a 0.422 Mb deletion on 2q24.2 that was diagnosed by comparative genomic hybridization and confirmed with fluorescent in situ hybridization (FISH). This deletion, which is present in approximately 61% of cells, includes three genes: TBR1, TANK, and PSMD14. The findings suggest that the critical region for intellectual disability and short stature in 2q24.2 can be narrowed to a 0.422 Mb segment. TBR1, a transcription factor involved in early cortical development, is a strong candidate for the intellectual disability phenotype seen in our patient and in patients with larger deletions in this region of the genome.
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http://dx.doi.org/10.1002/ajmg.a.35751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6868782PMC
April 2013

Phenotypic spectrum and genotype-phenotype correlations of NRXN1 exon deletions.

Eur J Hum Genet 2012 Dec 23;20(12):1240-7. Epub 2012 May 23.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Copy number variants (CNVs) and intragenic rearrangements of the NRXN1 (neurexin 1) gene are associated with a wide spectrum of developmental and neuropsychiatric disorders, including intellectual disability, speech delay, autism spectrum disorders (ASDs), hypotonia and schizophrenia. We performed a detailed clinical and molecular characterization of 24 patients who underwent clinical microarray analysis and had intragenic deletions of NRXN1. Seventeen of these deletions involved exons of NRXN1, whereas seven deleted intronic sequences only. The patients with exonic deletions manifested developmental delay/intellectual disability (93%), infantile hypotonia (59%) and ASDs (56%). Congenital malformations and dysmorphic features appeared infrequently and inconsistently among this population of patients with NRXN1 deletions. The more C-terminal deletions, including those affecting the β isoform of neurexin 1, manifested increased head size and a high frequency of seizure disorder (88%) when compared with N-terminal deletions of NRXN1.
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http://dx.doi.org/10.1038/ejhg.2012.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3499754PMC
December 2012

Prenatal chromosomal microarray analysis in a diagnostic laboratory; experience with >1000 cases and review of the literature.

Prenat Diagn 2012 Apr;32(4):351-61

Medical Genetics Laboratories, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

Objective: To evaluate the results of prenatal chromosomal microarray analysis (CMA) on >1000 fetal samples referred for testing at our institution and to compare these data to published reports.

Methods: High resolution CMA was offered to women undergoing amniocentesis or chorionic villus sampling. Parental samples were obtained concurrently to exclude maternal cell contamination and assist interpretation of copy number variations.

Results: Clinically significant copy number variations were observed in 85/1115 cases (7.6%) overall, and in 45/1075 cases (4.2 %) if 40 abnormal cases with known chromosome abnormalities or familial genomic imbalances were excluded. Eighteen of the 1115 cases had variants of unclear clinical significance (1.6%). Indications yielding the most clinically significant findings were abnormal karyotype/fluorescence in situ hybridization (26/61, 42.6%), family history of chromosomal abnormality (13/137, 9.5%), abnormal ultrasound (38/410, 9.3%), abnormal serum screening (2/37, 5.4%) and advanced maternal age (5/394, 1.3%). Of 1075 cases having no previously known cytogenetic abnormality or family history, 18 (1.7%) had clinically significant genomic changes undetectable by conventional prenatal chromosome analysis.

Conclusion: Current experience confirms that the detection rate of CMA for prenatal chromosomal abnormalities surpasses that of conventional karyotype analysis and continues to improve with higher resolution arrays, while maintaining a low frequency of results of unclear clinical significance.
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http://dx.doi.org/10.1002/pd.3861DOI Listing
April 2012

Observation and prediction of recurrent human translocations mediated by NAHR between nonhomologous chromosomes.

Genome Res 2011 Jan;21(1):33-46

Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

Four unrelated families with the same unbalanced translocation der(4)t(4;11)(p16.2;p15.4) were analyzed. Both of the breakpoint regions in 4p16.2 and 11p15.4 were narrowed to large ∼359-kb and ∼215-kb low-copy repeat (LCR) clusters, respectively, by aCGH and SNP array analyses. DNA sequencing enabled mapping the breakpoints of one translocation to 24 bp within interchromosomal paralogous LCRs of ∼130 kb in length and 94.7% DNA sequence identity located in olfactory receptor gene clusters, indicating nonallelic homologous recombination (NAHR) as the mechanism for translocation formation. To investigate the potential involvement of interchromosomal LCRs in recurrent chromosomal translocation formation, we performed computational genome-wide analyses and identified 1143 interchromosomal LCR substrate pairs, >5 kb in size and sharing >94% sequence identity that can potentially mediate chromosomal translocations. Additional evidence for interchromosomal NAHR mediated translocation formation was provided by sequencing the breakpoints of another recurrent translocation, der(8)t(8;12)(p23.1;p13.31). The NAHR sites were mapped within 55 bp in ∼7.8-kb paralogous subunits of 95.3% sequence identity located in the ∼579-kb (chr 8) and ∼287-kb (chr 12) LCR clusters. We demonstrate that NAHR mediates recurrent constitutional translocations t(4;11) and t(8;12) and potentially many other interchromosomal translocations throughout the human genome. Furthermore, we provide a computationally determined genome-wide "recurrent translocation map."
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http://dx.doi.org/10.1101/gr.111609.110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3012924PMC
January 2011

Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis.

Pediatrics 2008 Dec;122(6):1310-8

Baylor College of Medicine, Department of Molecular and Human Genetics, One Baylor Plaza, NAB 2015, Houston, TX 77030, USA.

Objectives: Our aim was to determine the frequency of genomic imbalances in neonates with birth defects by using targeted array-based comparative genomic hybridization, also known as chromosomal microarray analysis.

Methods: Between March 2006 and September 2007, 638 neonates with various birth defects were referred for chromosomal microarray analysis. Three consecutive chromosomal microarray analysis versions were used: bacterial artificial chromosome-based versions V5 and V6 and bacterial artificial chromosome emulated oligonucleotide-based version V6 Oligo. Each version had targeted but increasingly extensive genomic coverage and interrogated>150 disease loci with enhanced coverage in genomic rearrangement-prone pericentromeric and subtelomeric regions.

Results: Overall, 109 (17.1%) patients were identified with clinically significant abnormalities with detection rates of 13.7%, 16.6%, and 19.9% on V5, V6, and V6 Oligo, respectively. The majority of these abnormalities would not be defined by using karyotype analysis. The clinically significant detection rates by use of chromosomal microarray analysis for various clinical indications were 66.7% for "possible chromosomal abnormality"+/-"others" (other clinical indications), 33.3% for ambiguous genitalia+/-others, 27.1% for dysmorphic features+multiple congenital anomalies+/-others, 24.6% for dysmorphic features+/-others, 21.8% for congenital heart disease+/-others, 17.9% for multiple congenital anomalies+/-others, and 9.5% for the patients referred for others that were different from the groups defined. In all, 16 (2.5%) patients had chromosomal aneuploidies, and 81 (12.7%) patients had segmental aneusomies including common microdeletion or microduplication syndromes and other genomic disorders. Chromosomal mosaicism was found in 12 (1.9%) neonates.

Conclusions: Chromosomal microarray analysis is a valuable clinical diagnostic tool that allows precise and rapid identification of genomic imbalances and mosaic abnormalities as the cause of birth defects in neonates. Chromosomal microarray analysis allows for timely molecular diagnoses and detects many more clinically relevant genomic abnormalities than conventional cytogenetic studies, enabling more informed decision-making and management and appropriate assessment of recurrence risk.
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http://dx.doi.org/10.1542/peds.2008-0297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2795566PMC
December 2008

Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1, SIX6, and OTX2 resulting from a complex chromosomal rearrangement.

Am J Med Genet A 2008 Oct;146A(19):2480-9

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.

We report on a 26-month-old boy with developmental delay and multiple congenital anomalies, including many features suggestive of either branchiootorenal syndrome (BOR) or oculoauriculovertebral spectrum (OAVS). Chromosomal microarray analysis (CMA) initially revealed a copy-number gain with a single BAC clone (RP11-79M1) mapping to 14q23.1. FISH analysis showed that the third copy of this genomic region was inserted into the long arm of one chromosome 13. The same pattern was also seen in the chromosomes of the father, who has mental retardation, short stature, hypernasal speech, and minor craniofacial anomalies, including tall forehead, and crowded dentition. Subsequent whole genome oligonucleotide microarray analysis revealed an approximately 11.79 Mb duplication of chromosome 14q22.3-q23.3 and a loss of an approximately 4.38 Mb sequence in 13q21.31-q21.32 in both the propositus and his father and FISH supported the apparent association of the two events. Chromosome 14q22.3-q23.3 contains 51 genes, including SIX1, SIX6, and OTX2. A locus for branchiootic syndrome (BOS) has been mapped to 14q21.3-q24.3, and designated as branchiootic syndrome 3 (BOS3). Interestingly, mutations in SIX1 have been reported in patients with BOR/BOS3. We propose that the increased dosage of SIX1, SIX6, or OTX2 may be responsible for the BOR and OAVS-like features in this family.
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http://dx.doi.org/10.1002/ajmg.a.32398DOI Listing
October 2008

Identification of chromosome abnormalities in subtelomeric regions by microarray analysis: a study of 5,380 cases.

Am J Med Genet A 2008 Sep;146A(17):2242-51

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Subtelomeric imbalances are a significant cause of congenital disorders. Screening for these abnormalities has traditionally utilized GTG-banding analysis, fluorescence in situ hybridization (FISH) assays, and multiplex ligation-dependent probe amplification. Microarray-based comparative genomic hybridization (array-CGH) is a relatively new technology that can identify microscopic and submicroscopic chromosomal imbalances. It has been proposed that an array with extended coverage at subtelomeric regions could characterize subtelomeric aberrations more efficiently in a single experiment. The targeted arrays for chromosome microarray analysis (CMA), developed by Baylor College of Medicine, have on average 12 BAC/PAC clones covering 10 Mb of each of the 41 subtelomeric regions. We screened 5,380 consecutive clinical patients using CMA. The most common reasons for referral included developmental delay (DD), and/or mental retardation (MR), dysmorphic features (DF), multiple congenital anomalies (MCA), seizure disorders (SD), and autistic, or other behavioral abnormalities. We found pathogenic rearrangements at subtelomeric regions in 236 patients (4.4%). Among these patients, 103 had a deletion, 58 had a duplication, 44 had an unbalanced translocation, and 31 had a complex rearrangement. The detection rates varied among patients with a normal karyotype analysis (2.98%), with an abnormal karyotype analysis (43.4%), and with an unavailable or no karyotype analysis (3.16%). Six patients out of 278 with a prior normal subtelomere-FISH analysis showed an abnormality including an interstitial deletion, two terminal deletions, two interstitial duplications, and a terminal duplication. In conclusion, genomic imbalances at subtelomeric regions contribute significantly to congenital disorders. Targeted array-CGH with extended coverage (up to 10 Mb) of subtelomeric regions will enhance the detection of subtelomeric imbalances, especially for submicroscopic imbalances.
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http://dx.doi.org/10.1002/ajmg.a.32399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2680131PMC
September 2008

De novo and complex imbalanced chromosomal rearrangements revealed by array CGH in a patient with an abnormal phenotype and apparently "balanced" paracentric inversion of 14(q21q23).

Am J Med Genet A 2008 Aug;146A(15):1986-93

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas TX 77030, USA.

Paracentric inversions are one of the common chromosomal rearrangements typically associated with a normal phenotype. However, if dosage-sensitive genes are disrupted by the breakpoints, an abnormal phenotype could result. Detection of paracentric inversions often relies on careful high resolution banding, which has limited sensitivity. We report here cytogenetic studies performed on a 4-year-old female patient with global developmental delay, hypotonia, and dysmorphic features. The initial cytogenetic evaluation by G-banding revealed a de novo inversion of chromosome 14. Subsequent array CGH analysis using both a targeted BAC array and a high-resolution oligonucleotide array revealed microdeletions at the breakpoints of 14q21.1 (0.8 Mb) and 14q23.1 (0.9 Mb). Unexpectedly, a microdeletion in the region of 16q23.1 (1.3 Mb) was also identified, which overlaps with the common fragile site FRA16D. Parental chromosome and FISH analyses were normal, supporting the conclusion that these microdeletions were de novo in the patient and likely contributed to her abnormal phenotype. The case report presented illustrates the value of using high-resolution microarray analysis for phenotypically abnormal individuals with apparently balanced chromosomal rearrangements, including inversions.
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http://dx.doi.org/10.1002/ajmg.a.32408DOI Listing
August 2008

22q11.2 distal deletion: a recurrent genomic disorder distinct from DiGeorge syndrome and velocardiofacial syndrome.

Am J Hum Genet 2008 Jan;82(1):214-21

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

Microdeletions within chromosome 22q11.2 cause a variable phenotype, including DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS). About 97% of patients with DGS/VCFS have either a common recurrent approximately 3 Mb deletion or a smaller, less common, approximately 1.5 Mb nested deletion. Both deletions apparently occur as a result of homologous recombination between nonallelic flanking low-copy repeat (LCR) sequences located in 22q11.2. Interestingly, although eight different LCRs are located in proximal 22q, only a few cases of atypical deletions utilizing alternative LCRs have been described. Using array-based comparative genomic hybridization (CGH) analysis, we have detected six unrelated cases of deletions that are within 22q11.2 and are located distal to the approximately 3 Mb common deletion region. Further analyses revealed that the rearrangements had clustered breakpoints and either a approximately 1.4 Mb or approximately 2.1 Mb recurrent deletion flanked proximally by LCR22-4 and distally by either LCR22-5 or LCR22-6, respectively. Parental fluorescence in situ hybridization (FISH) analyses revealed that none of the available parents (11 out of 12 were available) had the deletion, indicating de novo events. All patients presented with characteristic facial dysmorphic features. A history of prematurity, prenatal and postnatal growth delay, developmental delay, and mild skeletal abnormalities was prevalent among the patients. Two patients were found to have a cardiovascular malformation, one had truncus arteriosus, and another had a bicuspid aortic valve. A single patient had a cleft palate. We conclude that distal deletions of chromosome 22q11.2 between LCR22-4 and LCR22-6, although they share some characteristic features with DGS/VCFS, represent a novel genomic disorder distinct genomically and clinically from the well-known DGS/VCF deletion syndromes.
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http://dx.doi.org/10.1016/j.ajhg.2007.09.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2253964PMC
January 2008

Validation of a targeted DNA microarray for the clinical evaluation of recurrent abnormalities in chronic lymphocytic leukemia.

Am J Hematol 2008 Jul;83(7):540-6

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77024, USA.

Recurrent genomic alterations, mainly losses and gains of specific chromosomes and/or regions, in chronic lymphocytic leukemia (CLL) are recognized as important independent predictors of prognosis and disease progression. The current standard clinical practice for identifying these alterations is chromosome analysis and in situ hybridization with probes targeting 4-5 chromosome regions. We sought to apply array comparative genomic hybridization (array-CGH) technology for the simultaneous detection of genomic imbalances of all loci implicated in CLL. DNA from enriched B-cells from CLL patients were analyzed by array-CGH on a customized CLL BAC array. Copy number changes were detected in 87% of samples with a sensitivity of 100% in samples with clonal abnormalities present in at least 23% of the cells. Furthermore, in nine cases genomic alterations were observed that were undetectable by standard cytogenetic and/or FISH analyses. One of these patients had a 13q14 deletion that was missed by the clinical CLL FISH panel probe set. Our results suggest that a subset of potentially significant genomic alterations in CLL is being missed by the current available techniques. Furthermore, this pilot study clearly shows the robustness, high sensitivity, and high specificity for the targeted CLL microarray analysis as well as the potential for use in routine screening in CLL.
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http://dx.doi.org/10.1002/ajh.21145DOI Listing
July 2008

Mosaic tetrasomy 12p with triplication of 12p detected by array-based comparative genomic hybridization of peripheral blood DNA.

Am J Med Genet A 2007 Dec;143A(24):2910-5

Section of Medical and Molecular Genetics, Department of Pediatrics, University of Arizona, Tucson, Arizona, USA.

A patient whose dysmorphism at birth was not diagnostic for Pallister-Killian syndrome (PKS) was found to have mosaic tetrasomy 12p by an array-based comparative genomic hybridization of peripheral blood DNA. He was determined to be mosaic for 46,XY,trp(12)(p11.2 --> p13) in cultured skin fibroblasts. His appearance was typical for PKS at 4 months of age.
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http://dx.doi.org/10.1002/ajmg.a.31959DOI Listing
December 2007

Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics.

Am J Med Genet A 2007 Aug;143A(15):1679-86

Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, Texas 77030.

Somatic chromosomal mosaicism is a well-established cause for birth defects, mental retardation, and, in some instances, specific genetic syndromes. We have developed a clinically validated, targeted BAC clone array as a platform for comparative genomic hybridization (aCGH) to enable detection of a wide range of pathologic copy number changes in DNA. It is designed to provide high sensitivity to detect well-characterized submicroscopic micro-deletion and duplication disorders while at the same time minimizing detection of variation of uncertain clinical significance. In the course of studying 2,585 samples submitted to our clinical laboratory, chromosomal mosaicism was detected in 12 patient samples; 10 of these cases were reported to have had a normal blood chromosome analysis. This enhanced ability of aCGH to detect mosaicism missed by routine chromosome analysis may be due to some combination of testing multiple cell lineages and/or failure of cytogenetically abnormal T lymphocytes to respond to mitogens. This suggests that aCGH may detect somatic chromosomal mosaicism that would be missed by conventional cytogenetics.
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http://dx.doi.org/10.1002/ajmg.a.31740DOI Listing
August 2007

Clinical implementation of chromosomal microarray analysis: summary of 2513 postnatal cases.

PLoS One 2007 Mar 28;2(3):e327. Epub 2007 Mar 28.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.

Background: Array Comparative Genomic Hybridization (a-CGH) is a powerful molecular cytogenetic tool to detect genomic imbalances and study disease mechanism and pathogenesis. We report our experience with the clinical implementation of this high resolution human genome analysis, referred to as Chromosomal Microarray Analysis (CMA).

Methods And Findings: CMA was performed clinically on 2513 postnatal samples from patients referred with a variety of clinical phenotypes. The initial 775 samples were studied using CMA array version 4 and the remaining 1738 samples were analyzed with CMA version 5 containing expanded genomic coverage. Overall, CMA identified clinically relevant genomic imbalances in 8.5% of patients: 7.6% using V4 and 8.9% using V5. Among 117 cases referred for additional investigation of a known cytogenetically detectable rearrangement, CMA identified the majority (92.5%) of the genomic imbalances. Importantly, abnormal CMA findings were observed in 5.2% of patients (98/1872) with normal karyotypes/FISH results, and V5, with expanded genomic coverage, enabled a higher detection rate in this category than V4. For cases without cytogenetic results available, 8.0% (42/524) abnormal CMA results were detected; again, V5 demonstrated an increased ability to detect abnormality. Improved diagnostic potential of CMA is illustrated by 90 cases identified with 51 cryptic microdeletions and 39 predicted apparent reciprocal microduplications in 13 specific chromosomal regions associated with 11 known genomic disorders. In addition, CMA identified copy number variations (CNVs) of uncertain significance in 262 probands; however, parental studies usually facilitated clinical interpretation. Of these, 217 were interpreted as familial variants and 11 were determined to be de novo; the remaining 34 await parental studies to resolve the clinical significance.

Conclusions: This large set of clinical results demonstrates the significantly improved sensitivity of CMA for the detection of clinically relevant genomic imbalances and highlights the need for comprehensive genetic counseling to facilitate accurate clinical correlation and interpretation.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0000327PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1828620PMC
March 2007

Evidence for involvement of TRE-2 (USP6) oncogene, low-copy repeat and acrocentric heterochromatin in two families with chromosomal translocations.

Hum Genet 2006 Sep 22;120(2):227-37. Epub 2006 Jun 22.

Department of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm T821, Houston, TX 77030, USA.

We report clinical findings and molecular cytogenetic analyses for two patients with translocations [t(14;17)(p12;p12) and t(15;17)(p12;p13.2)], in which the chromosome 17 breakpoints map at a large low-copy repeat (LCR) and a breakage-prone TRE-2 (USP6) oncogene, respectively. In family 1, a 6-year-old girl and her 5-year-old brother were diagnosed with mental retardation, short stature, dysmorphic features, and Charcot-Marie-Tooth disease type 1A (CMT1A). G-banding chromosome analysis showed a der(14)t(14;17)(p12;p12) in both siblings, inherited from their father, a carrier of the balanced translocation. Chromosome microarray and FISH analyses revealed that the PMP22 gene was duplicated. The chromosome 17 breakpoint was mapped within an approximately 383 kb LCR17pA that is known to also be the site of several breakpoints of different chromosome aberrations including the evolutionary translocation t(4;19) in Gorilla gorilla. In family two, a patient with developmental delay, subtle dysmorphic features, ventricular enlargement with decreased periventricular white matter, mild findings of bilateral perisylvian polymicrogyria and a very small anterior commissure, a cryptic duplication including the Miller-Dieker syndrome region was identified by chromosome microarray analysis. The chromosome 17 breakpoint was mapped by FISH at the TRE-2 oncogene. Both partner chromosome breakpoints were mapped on the short arm acrocentric heterochromatin within or distal to the rRNA cluster, distal to the region commonly rearranged in Robertsonian translocations. We propose that TRE-2 together with LCR17pA, located approximately 10 Mb apart, also generated the evolutionary gorilla translocation t(4;19). Our results support previous observations that the USP6 oncogene, LCRs, and repetitive DNA sequences play a significant role in the origin of constitutional chromosome aberrations and primate genome evolution.
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http://dx.doi.org/10.1007/s00439-006-0200-7DOI Listing
September 2006
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