197 results on '"Sanger WG"'
Search Results
2. Occurrence of the t(2;5)(p23;q35) in non-Hodgkin's lymphoma
- Author
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Weisenburger, DD, primary, Gordon, BG, additional, Vose, JM, additional, Bast, MA, additional, Chan, WC, additional, Greiner, TC, additional, Anderson, JR, additional, and Sanger, WG, additional
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- 1996
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3. Bone marrow transplantation for peripheral T-cell lymphoma in children and adolescents
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Gordon, BG, primary, Warkentin, PI, additional, Weisenburger, DD, additional, Vose, JM, additional, Sanger, WG, additional, Strandjord, SE, additional, Anderson, JR, additional, Verdirame, JD, additional, Bierman, PJ, additional, and Armitage, JO, additional
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- 1992
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4. Pontine tegmental cap dysplasia with a 2q13 microdeletion involving the NPHP1 gene: insights into malformations of the mid-hindbrain.
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Macferran KM, Buchmann RF, Ramakrishnaiah R, Griebel ML, Sanger WG, Saronwala A, and Schaefer GB
- Abstract
The case of a young man with multiple brain and somatic anomalies that presented diagnostic difficulties, is discussed in this report. A majority of his features were suggestive of Joubert syndrome--although it was felt that he did not fully meet diagnostic criteria. The subsequent evaluations included a magnetic resonance image of the brain, that was found to be consistent with pontine tegmental cap dysplasia. Chromosomal microarray studies showed a 2q13 deletion. A gene associated with Joubert syndrome, NPHP1, is within this region. This case highlights several important aspects of the diagnosis and nosology of malformations of the mid-hind brain. © 2010 Elsevier Inc. All rights reserved. [ABSTRACT FROM AUTHOR]
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- 2010
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5. Chromosomal abnormalities in untreated patients with non-Hodgkin's lymphoma: associations with histology, clinical characteristics, and treatment outcome. The Nebraska Lymphoma Study Group
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Schouten, HC, primary, Sanger, WG, additional, Weisenburger, DD, additional, Anderson, J, additional, and Armitage, JO, additional
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- 1990
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6. Overview of genetics and role of the pediatric physical therapist in the diagnostic process.
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Sanger WG, Dave B, and Stuberg W
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- 2001
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7. The effects of infertility on parent-child relationships and adjustment.
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Allen KD, Maguire KB, Williams GE, and Sanger WG
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- 1996
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8. Intermediate lymphocytic lymphoma: immunophenotypic and cytogenetic findings
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Weisenburger, DD, Sanger, WG, Armitage, JO, and Purtilo, DT
- Abstract
A detailed immunohistologic and cytogenetic analysis of 12 cases of intermediate lymphocytic lymphoma was performed. The characteristic immunophenotype of intermediate lymphocytic lymphoma was: surface IgM and IgD+, BA1+, B1+, BA2-, B2-, B4+, Leu 14+, Leu 1+, HLA-DR+, and common acute lymphocytic leukemia associated (CALLA) antigen negative. Clonal chromosome abnormalities were identified in ten cases, with structural or numerical abnormalities of chromosomes 11 or 12 in nine cases. Five cases had structural abnormalities involving the long arm of chromosome 11; three of these had translocations with chromosome 14 at band q32. Three cases had trisomy 12, and one case had a translocation involving the long arm of chromosome 12. The tenth case had a translocation involving the long arms of chromosomes 7 and 9. These characteristic immunophenotypic and cytogenetic findings suggest a close lineage relationship between intermediate lymphocytic lymphoma and small lymphocytic (well differentiated) lymphoma/chronic lymphocytic leukemia. Their differing clinical, cytologic, and architectural features suggest, however, that intermediate lymphocytic lymphoma should be considered a separate category of lymphocytic lymphoma in the International Working Formulation.
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- 1987
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9. Chromosomal abnormalities in Hodgkin's disease
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Schouten, HC, Sanger, WG, Duggan, M, Weisenburger, DD, MacLennan, KA, and Armitage, JO
- Abstract
Numerous neoplastic states have associated or causal cytogenetic abnormalities. In some cancers, specific chromosomal abnormalities appear to correlate with the clinical characteristics and prognosis. Cytogenetic analysis of Hodgkin's disease is thought to be technically difficult and only a small number of cases with evaluable results have been reported. We have attempted cytogenetic studies of lymph nodes from 37 patients with Hodgkin's disease. In 29 of the 37 patients (78%), successful chromosomal analysis was accomplished. Chromosomal abnormalities were found in 13 patients (45%); five of these patients had been previously treated with chemotherapy. Numerical changes were found in all patients, most commonly involving chromosomes 5, 9, 15, 18, 22, X, and marker chromosomes. Seven patients also had structural abnormalities. The breakpoints 4q32–34, 6q24, 12q13, 12q23–24, and 13p11–13 were each seen in at least two patients. All but two patients had an admixture of normal cells. Three patients had two or more clones, and one had subclones. No statistically significant correlations between chromosomal abnormalities and clinical characteristics were demonstrated, although the number of patients in each subgroup was small. We conclude that chromosomal studies of Hodgkin's disease are likely to be successful. Additional studies are needed to correlate the karyotypical abnormalities in Hodgkin's disease with clinical and biological characteristics.
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- 1989
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10. PURGING OF PERIPHERAL-BLOOD PROGENITOR CELLS WITH ANTISENSE OLIGONUCLEOTIDE-DIRECTED AGAINST BCR-ABL FOR CHRONIC MYELOGENOUS LEUKEMIA
- Author
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BISHOP, MR, Joshi, Ss, Jackson, Jd, Wu, Ag, Sanger, Wg, Patrick Iversen, Bayever, E., Sharp, Jg, Zon, G., and Kessinger, A.
11. Variable expressivity of a novel mutation in the SCN1A gene leading to an autosomal dominant seizure disorder.
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Mhanni AA, Hartley JN, Sanger WG, Chudley AE, and Spriggs EL
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- 2011
12. Intraocular inflammatory myofibroblastic tumor with alk overexpression.
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O'malley DP, Poulos C, Czader M, Sanger WG, and Orazi A
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We report a case of an intraocular inflammatory myofibroblastic tumor nearly filling the vitreous cavity of the eye of a 50-year-old man. The tumor was composed of a mixture of spindle cells and mixed inflammatory elements, including numerous plasma cells. The differential diagnosis included inflammatory pseudotumor and neoplastic mimics of this condition. Further investigation with immunohistochemistry revealed the mass to be composed of myofibroblasts, positive for smooth muscle actin stains and with weak anaplastic lymphoma kinase (ALK) expression in some tumor cells. Evaluation by fluorescence in situ hybridization revealed the tumor cells to have multiple copies of chromosome 2 and ALK but no rearrangement of the ALK gene. The authors propose that multiple copies of the ALK gene may be involved in inflammatory myofibroblastic tumor tumorigenesis, in addition to ALK gene rearrangements. [ABSTRACT FROM AUTHOR]
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- 2004
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13. Karyotypic abnormalities associated with Epstein-Barr virus status in classical Hodgkin lymphoma.
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Montgomery ND, Coward WB 4th, Johnson S, Yuan J, Gulley ML, Mathews SP, Kaiser-Rogers K, Rao KW, Sanger WG, Sanmann JN, and Fedoriw Y
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- Hodgkin Disease genetics, Humans, Herpesvirus 4, Human physiology, Hodgkin Disease virology, Karyotyping
- Abstract
Classical Hodgkin lymphoma (CHL) is morphologically characterized by scattered malignant Hodgkin/Reed-Sternberg (HRS) cells that are far outnumbered by surrounding reactive hematolymphoid cells. Approximately half of all cases of CHL are associated with infection by Epstein-Barr virus (EBV), an oncogenic herpesvirus that expresses a number of proteins thought to contribute to transformation. While a small number of published studies have attempted to identify recurrent cytogenetic abnormalities in CHL, no large case series have explored karyotypic differences between EBV-positive and EBV-negative tumors. Here, we report a two-institution retrospective investigation of cytogenetic features characterizing CHL. In our cohort, cases of EBV-negative CHL were characterized by more complex routine karyotypes than their EBV-positive counterparts (24.6 versus 15.6 independent aberrations per case, P = 0.009). The increased complexity of EBV-negative cases was driven by a number of features suggestive of genomic instability, including a larger number of independent chromosomal breakpoints (P = 0.03) and apparently aneuploid autosomes (P = 0.008). Compelling but nonsignificant trends also suggest a larger modal number and increased marker chromosomes in EBV-negative cases (P = 0.13 and 0.06, respectively). While some of these differences are related to histologic subtype, others appear independent of histology. Finally, a significant subset of EBV-positive tumors has a surprisingly simple karyotype relative to what is normally seen in CHL, an observation suggesting considerable biological and genetic diversity in this disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)
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- 2016
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14. Section E6.5-6.8 of the ACMG technical standards and guidelines: chromosome studies of lymph node and solid tumor-acquired chromosomal abnormalities.
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Cooley LD, Morton CC, Sanger WG, Saxe DF, and Mikhail FM
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- Bone Marrow pathology, Cytodiagnosis standards, Cytogenetic Analysis standards, Genomics standards, Guidelines as Topic, Humans, Laboratories standards, Neoplasms pathology, United States, Chromosome Aberrations, Genetic Testing standards, Neoplasms diagnosis, Neoplasms genetics
- Abstract
Disclaimer: These ACMG standards and guidelines are developed primarily as an educational resource for clinical laboratory geneticists to help them provide quality clinical laboratory genetic services. Adherence to these standards and guidelines is voluntary and does not necessarily ensure a successful medical outcome. These standards and guidelines should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinical laboratory geneticist should apply his or her own professional judgment to the specific circumstances presented by the individual patient or specimen. Clinical laboratory geneticists are encouraged to document in the patient's record the rationale for the use of a particular procedure or test, whether or not it is in conformance with these standards and guidelines. They also are advised to take notice of the date any particular guideline was adopted, and to consider other relevant medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.Cytogenetic analysis of tumor tissue is performed to detect and characterize chromosomal aberrations to aid histopathological and clinical diagnosis and patient management. At the time of diagnosis, known recurrent clonal aberrations may facilitate histopathological diagnosis and subtyping of the tumor. This information may contribute to clinical therapeutic decisions. However, even when tumors have a known recurrent clonal aberration, each tumor is genetically unique and probably heterogeneous. It is important to discover as much about the genetics of a tumor at diagnosis as is possible with the methods available for study of the tumor material. The information gathered at initial study will inform follow-up studies, whether for residual disease detection, determination of relapse and clonal evolution, or identifying a new disease clone.This updated Section E6.5-6.8 has been incorporated into and supersedes the previous Sections E6.4 and E6.5 in Section E: Clinical Cytogenetics of the 2009 Edition (Revised 01/2010), American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories. This section deals specifically with the standards and guidelines applicable to lymph node and solid tumor chromosome analysis.Genet Med 18 6, 643-648.
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- 2016
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15. Breast Cancer and Non-Hodgkin Lymphoma in a Young Male with Cowden Syndrome.
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Hagelstrom RT, Ford J, Reiser GM, Nelson M, Pickering DL, Althof PA, Sanger WG, and Coccia PF
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- Adult, Child, Hamartoma Syndrome, Multiple genetics, Humans, Male, Pedigree, Breast Neoplasms, Male complications, Hamartoma Syndrome, Multiple complications, Lymphoma, Non-Hodgkin complications
- Abstract
Male breast cancer (MBC) is unusual, especially in young adults. Most cases of MBC as a secondary malignancy relate to the previous treatment with ionizing radiation. MBC can be associated with mutations in hereditary cancer predisposition syndrome genes (i.e., BRCA2); however, no such association has been reported in patients with Cowden syndrome (involving the phosphatase and tensin homolog [PTEN] gene). We describe a patient with Cowden syndrome who was initially diagnosed with B-cell lymphoblastic lymphoma at the age of 7 years, then MBC at the age of 31 years, and never received radiation therapy., (© 2015 Wiley Periodicals, Inc.)
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- 2016
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16. Assessing the utility of confirmatory studies following identification of large-scale genomic imbalances by microarray.
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Sanmann JN, Pickering DL, Golden DM, Stevens JM, Hempel TE, Althof PA, Wiggins ML, Starr LJ, Davé BJ, and Sanger WG
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- DNA Copy Number Variations, Gene Dosage, Gene Duplication, Genome, Human, Humans, In Situ Hybridization, Fluorescence, Oligonucleotide Array Sequence Analysis methods, Polymorphism, Single Nucleotide, Reproducibility of Results, Retrospective Studies, Sequence Deletion, Allelic Imbalance, Genomics methods, Genomics standards
- Abstract
Purpose: The identification of clinically relevant genomic dosage anomalies assists in accurate diagnosis, prognosis, and medical management of affected individuals. Technological advancements within the field, such as the advent of microarray, have markedly increased the resolution of detection; however, clinical laboratories have maintained conventional techniques for confirmation of genomic imbalances identified by microarray to ensure diagnostic accuracy. In recent years the utility of this confirmatory testing of large-scale aberrations has been questioned but has not been scientifically addressed., Methods: We retrospectively reviewed 519 laboratory cases with genomic imbalances meeting reportable criteria by microarray and subsequently confirmed with a second technology, primarily fluorescence in situ hybridization., Results: All genomic imbalances meeting reportable criteria detected by microarray were confirmed with a second technology. Microarray analysis generated no false-positive results., Conclusion: Confirmatory testing of large-scale genomic imbalances (deletion of ≥150 kb, duplication of ≥500 kb) solely for the purpose of microarray verification may be unwarranted. In some cases, however, adjunct testing is necessary to overcome limitations inherent to microarray. A recommended clinical strategy for adjunct testing following identified genomic imbalances using microarray is detailed.
- Published
- 2015
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17. The role of candidate-gene CNTNAP2 in childhood apraxia of speech and specific language impairment.
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Centanni TM, Sanmann JN, Green JR, Iuzzini-Seigel J, Bartlett C, Sanger WG, and Hogan TP
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- Adolescent, Child, Child, Preschool, Female, Gene Deletion, Genetic Variation, Humans, Male, Membrane Proteins deficiency, Nerve Tissue Proteins deficiency, Speech physiology, Speech Disorders genetics, Apraxias genetics, Language Development Disorders genetics, Membrane Proteins genetics, Nerve Tissue Proteins genetics
- Abstract
Childhood apraxia of speech (CAS) is a debilitating pediatric speech disorder characterized by varying symptom profiles, comorbid deficits, and limited response to intervention. Specific Language Impairment (SLI) is an inherited pediatric language disorder characterized by delayed and/or disordered oral language skills including impaired semantics, syntax, and discourse. To date, the genes associated with CAS and SLI are not fully characterized. In the current study, we evaluated behavioral and genetic profiles of seven children with CAS and eight children with SLI, while ensuring all children were free of comorbid impairments. Deletions within CNTNAP2 were found in two children with CAS but not in any of the children with SLI. These children exhibited average to high performance on language and word reading assessments in spite of poor articulation scores. These findings suggest that genetic variation within CNTNAP2 may be related to speech production deficits., (© 2015 Wiley Periodicals, Inc.)
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- 2015
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18. Papillary tumor of the pineal region with synchronous suprasellar focus and novel cytogenetic features.
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Mobley BC, Kumar M, Sanger WG, Nelson M, Nickols HH, Chambless LB, and Gokden M
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- Adult, Combined Modality Therapy, Cytogenetic Analysis, Humans, Male, Neurosurgical Procedures, Pinealoma therapy, Radiotherapy, Carcinoma, Papillary genetics, Carcinoma, Papillary pathology, Pinealoma genetics, Pinealoma pathology
- Abstract
Papillary tumor of the pineal region (PTPR) is an uncommon neoplasm with variable biologic behavior. Cytogenetic and molecular diagnostic studies are rare, yielding no definitive genetic signature. We report a case of PTPR with a multicentric presentation and unusual cytogenetic features. A 25-year-old man presented with headache, disconjugate gaze, and confusion. Mass lesions in the pineal and suprasellar regions, with identical imaging characteristics, were identified. The former extended partially into the fourth ventricle. It showed typical PTPR histology and losses of chromosomes 3, 7, 10, 14, 18, and Y with gains of chromosomes 3, 8, and 9. Seventeen months postsurgery, the patient is stable without disease progression after radiation therapy. Synchronous mass lesions at presentation and losses of chromosomes 3, 7, 14, 18, and Y are unusual features, adding to the available data and underscoring the biologic and genetic variability associated with these neoplasms., (Copyright © 2015 Elsevier Inc. All rights reserved.)
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- 2015
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19. Isolated MYC cytogenetic abnormalities in diffuse large B-cell lymphoma do not predict an adverse clinical outcome.
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Caponetti GC, Dave BJ, Perry AM, Smith LM, Jain S, Meyer PN, Bast M, Bierman PJ, Bociek RG, Vose JM, Armitage JO, Aoun P, Fu K, Greiner TC, Chan WC, Sanger WG, and Weisenburger DD
- Subjects
- Adult, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor, Chromosome Banding, Female, Gene Rearrangement, B-Lymphocyte, Genes, bcl-2, Humans, In Situ Hybridization, Fluorescence, Lymphoma, Large B-Cell, Diffuse drug therapy, Lymphoma, Large B-Cell, Diffuse pathology, Male, Middle Aged, Neoplasm Staging, Prognosis, Proto-Oncogene Proteins c-bcl-6 genetics, Survival Analysis, Treatment Outcome, Young Adult, Chromosome Aberrations, Genes, myc, Lymphoma, Large B-Cell, Diffuse genetics, Lymphoma, Large B-Cell, Diffuse mortality
- Abstract
In this study, we investigated the significance of MYC, BCL2 and BCL6 gene abnormalities in a cohort of 205 diffuse large B-cell lymphoma (DLBCL) patients studied by conventional and/or fluorescence in situ hybridization cytogenetic analysis. Combining these methods, 172 cases (84%) were classified as MYC-, 17 (8%) were MYC+/BCL2-/BCL6-, and 16 (8%) were double/triple-hit lymphomas (i.e. MYC+/BCL2+, MYC+/BCL6+, or MYC+/BCL2+/BCL6+). We found a significant difference in event-free survival (EFS) among the three groups (p = 0.02), with the double/triple-hit group having the worst EFS. Patients who were MYC+, but BCL2- and BCL6-, had the best EFS. We conclude that patients with MYC+ DLBCL, but without BCL2 or BCL6 abnormalities, do not have a worse outcome when compared to those who are MYC-. However, patients with double/triple-hit DLBCL have a very poor outcome and should be treated with aggressive or novel therapies.
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- 2015
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20. Aplastic Anemia in Two Patients with Sex Chromosome Aneuploidies.
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Rush ET, Schaefer GB, Sanger WG, and Coccia PF
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- Adolescent, Anemia, Aplastic immunology, Anemia, Aplastic pathology, Anemia, Aplastic therapy, Bone Marrow Transplantation, Child, Preschool, Chromosomes, Human, X genetics, Craniofacial Abnormalities immunology, Craniofacial Abnormalities pathology, Craniofacial Abnormalities therapy, Female, Graft Survival, Humans, Intellectual Disability immunology, Intellectual Disability pathology, Intellectual Disability therapy, Karyotyping, Opportunistic Infections immunology, Opportunistic Infections pathology, Opportunistic Infections therapy, Sex Chromosome Aberrations, Sex Chromosome Disorders of Sex Development pathology, Treatment Outcome, Trisomy pathology, Anemia, Aplastic genetics, Craniofacial Abnormalities genetics, Intellectual Disability genetics, Opportunistic Infections genetics, Sex Chromosome Disorders of Sex Development genetics, Trisomy genetics
- Abstract
Sex chromosome aneuploidies range in incidence from rather common to exceedingly rare and have a variable phenotype. We report 2 patients with sex chromosome aneuploidies who developed severe aplastic anemia requiring treatment. The first patient had tetrasomy X (48,XXXX) and presented at 9 years of age, and the second patient had trisomy X (47,XXX) and presented at 5 years of age. Although aplastic anemia has been associated with other chromosomal abnormalities, sex chromosome abnormalities have not been traditionally considered a risk factor for this condition. A review of the literature reveals that at least one other patient with a sex chromosome aneuploidy (45,X) has suffered from aplastic anemia and that other autosomal chromosomal anomalies have been described. Despite the uncommon nature of each condition, it is possible that the apparent association is coincidental. A better understanding of the genetic causes of aplastic anemia remains important., (© 2015 S. Karger AG, Basel.)
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- 2015
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21. Cytosine arabinoside and mitoxantrone followed by second allogeneic transplant for the treatment of children with refractory juvenile myelomonocytic leukemia.
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Patel SA, Coulter DW, Grovas AC, Gordon BG, Harper JL, Warkentin PI, Wisecarver JL, Sanger WG, and Coccia PF
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- Antimetabolites, Antineoplastic administration & dosage, Child, Child, Preschool, Combined Modality Therapy, Disease-Free Survival, Humans, Infant, Male, Recurrence, Retreatment, Tissue Donors, Transplantation Chimera, Transplantation Conditioning methods, Transplantation, Homologous, Cytarabine administration & dosage, Hematopoietic Stem Cell Transplantation, Leukemia, Myelomonocytic, Juvenile drug therapy, Leukemia, Myelomonocytic, Juvenile therapy, Mitoxantrone administration & dosage
- Abstract
Hematopoietic stem cell transplantation (HSCT) remains the only curative option for most patients with juvenile myelomonocytic leukemia (JMML). However, persistent disease and relapse rates after transplant range from 26% to 58%. We report the successful use of second HSCT after preparation with mitoxantrone and cytosine arabinoside (Ara-C) for patients with refractory or recurrent disease. Between 1993 and 2006, 5 children who underwent HSCT at our institution as initial therapy for JMML had persistent disease or relapsed. Pre-HSCT conditioning varied and donors were either HLA-matched siblings (n=2) or matched unrelated donors (n=3). After initial HSCT, they subsequently received high-dose Ara-C (3 g/m IV) every 12 hours on days -8 through -3 and mitoxantrone (10 mg/m/d IV) on days -8, -7, -6 followed by second HSCT from their original donors. All 5 patients are alive at 88, 179, 199, 234, and 246 months with no evidence of JMML, no significant toxicity, and 100% donor chimera as determined by PCR short-tandem repeat analysis. Our experience supports second transplant utilizing high-dose Ara-C and mitoxantrone in children with JMML who do not respond or relapse after first transplant.
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- 2014
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22. Duplication of 20qter and deletion of 20pter due to paternal pericentric inversion: patient report and review of 20qter duplications.
- Author
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Starr LJ, Truemper EJ, Pickering DL, Sanger WG, and Olney AH
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- Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Chromosome Mapping, Comparative Genomic Hybridization, Humans, Infant, Newborn, Karyotyping, Male, Phenotype, Chromosome Deletion, Chromosome Duplication, Chromosome Inversion, Chromosomes, Human, Pair 20
- Abstract
Duplications of the terminal long arm of chromosome 20 are rare chromosomal anomalies. We report a male infant found on array comparative genomic hybridization analysis to have a 19.5 Mb duplication of chromosome 20q13.12-13.33, as well as an 886 kb deletion of 20p13 at 18,580-904,299 bp. This anomaly occurred as the recombinant product of a paternal pericentric inversion. There have been 23 reported clinical cases involving 20qter duplications; however, to our knowledge this is only the second reported patient with a paternal pericentric inversion resulting in 46,XY,rec(20)dup(20q). This patient shares many characteristics with previously described patients with 20qter duplications, including microphthalmia, anteverted nares, long ears, cleft palate, small chin, dimpled chin, cardiac malformations, and normal intrauterine growth. While there is variable morbidity in patients with terminal duplications of 20q, a review of previously reported patients and comparison to our patient's findings shows significant phenotypic similarity., (© 2014 Wiley Periodicals, Inc.)
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- 2014
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23. Allogeneic stem cell transplantation for Philadelphia chromosome-positive acute myeloid leukemia.
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Bhatt VR, Akhtari M, Bociek RG, Sanmann JN, Yuan J, Dave BJ, Sanger WG, Kessinger A, and Armitage JO
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- Adult, Antibiotics, Antineoplastic therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Benzamides therapeutic use, Consolidation Chemotherapy, Cyclophosphamide therapeutic use, Cytarabine therapeutic use, Female, Graft vs Host Disease drug therapy, Humans, Idarubicin therapeutic use, Imatinib Mesylate, Induction Chemotherapy, Leukemia, Myelogenous, Chronic, BCR-ABL Positive genetics, Leukemia, Myelogenous, Chronic, BCR-ABL Positive mortality, Male, Middle Aged, Piperazines therapeutic use, Protein Kinase Inhibitors therapeutic use, Pyrimidines therapeutic use, Transplantation, Homologous, Treatment Outcome, Young Adult, Hematopoietic Stem Cell Transplantation, Immunosuppressive Agents therapeutic use, Leukemia, Myelogenous, Chronic, BCR-ABL Positive therapy, Philadelphia Chromosome
- Abstract
Philadelphia chromosome-positive acute myeloid leukemia (Ph(+)-AML) has a poor response to anthracycline- and cytarabine-containing regimens, high relapse rate, and dismal prognosis. Although therapy with imatinib and allogeneic stem cell transplantation (allo-SCT) is promising, relatively short follow-up limits understanding of long-term results of these therapies. This report describes the outcomes of 3 cases of Ph(+)-AML diagnosed and transplanted at the University of Nebraska Medical Center between 2004 and 2011. These patients, young and without major comorbidities, received induction therapy with 7 days of cytarabine and 3 days of idarubicin along with imatinib and consolidation therapy with high-dose cytarabine (with or without imatinib). All patients underwent 10/10 HLA-matched peripheral blood allo-SCT (sibling donor for first and third patients and unrelated donor for the second patient; all had acute graft-versus-host disease (GVHD), and the first and third patients had chronic GVHD. All patients are currently alive and experiencing complete remission at 116, 113, and 28 months after diagnosis, respectively. This report shows that the use of allo-SCT with resultant graft-versus-leukemia effect and the addition of imatinib can result in long-term remission and possible cure in some patients with Ph(+)-AML., (Copyright © 2014 by the National Comprehensive Cancer Network.)
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- 2014
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24. Occurrence of nephroblastomatosis with dup(18)(q11.2-q23) implicates trisomy 18 tumor screening protocol in select patients with 18q duplication.
- Author
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Starr LJ, Sanmann JN, Olney AH, Wandoloski M, Sanger WG, and Coulter DW
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- Child, Preschool, Humans, Male, Trisomy 18 Syndrome, Chromosomes, Human, Pair 18 genetics, Fetal Macrosomia genetics, Gene Duplication, Trisomy genetics, Wilms Tumor genetics
- Abstract
Duplications of the long arm of chromosome 18 have been previously reported in patients with phenotypic findings similar to full trisomy 18. Trisomy 18 increases the risk for Wilms tumor and it is currently recommended that these patients undergo abdominal ultrasonography screening every 6 months. We report on nephroblastomatosis in a 27-month-old male with a 55 Mb duplication of chromosome 18q11.2-q23 (chr18:22693370-77982126, hg 19) and propose that the trisomy 18 tumor screening protocol could also benefit patients with large 18q duplications., (© 2014 Wiley Periodicals, Inc.)
- Published
- 2014
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25. Report of a patient with developmental delay, hearing loss, growth retardation, and cleft lip and palate and a deletion of 7q34-36.1: review of distal 7q deletions.
- Author
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Rush ET, Stevens JM, Sanger WG, and Olney AH
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- Child, Female, Humans, In Situ Hybridization, Fluorescence, Karyotyping, Syndrome, Chromosome Deletion, Chromosomes, Human, Pair 7, Cleft Lip genetics, Cleft Palate genetics, Developmental Disabilities genetics, Hearing Loss genetics
- Abstract
The use of aCGH has improved our ability to find subtle cytogenetic abnormalities as well as to find more precise information in patients with previously known abnormalities. In addition, it has allowed more specific genotype-phenotype correlation. In this report we describe a patient with a chromosomal deletion initially diagnosed with conventional cytogenetic analysis which was redemonstrated and more specifically described upon aCGH analysis. Our patient is a 12-year-old female born to a 26-year-old G1P0 mother. She was noted as a neonate to have a bilateral cleft lip and cleft palate, abnormal external ears, dysmorphic facies, and moderate to severe hearing loss. She has subsequently shown developmental delay, hyperreflexia, seizures, hyperactivity, and absence of speech. Chromosomal analysis showed deletion of 7q34q36.1. FISH studies confirmed the deletion was interstitial. Parental chromosomes were performed and did not show any cytogenetic abnormalities. aCGH was recently performed for the patient to further characterize the breakpoints of the deletion and confirmed the deletion was interstitial and of 13.2 Mb in size. Both proximal and terminal 7q deletion show a different phenotype than that of our patient. A number of patients with similar deletions have been found and while significant variability is observed, a number of findings appear to be common to deletions in this region. Therefore, we feel that distal interstitial deletions of chromosome 7q represent a recognizable phenotype and could be considered a separate deletion syndrome., (Copyright © 2013 Wiley Periodicals, Inc.)
- Published
- 2013
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26. Differences in the cytogenetic alteration profiles of diffuse large B-cell lymphoma among Chinese and American patients.
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Chen Y, Dave BJ, Zhu X, Chan WC, Iqbal J, Sanger WG, and Fu K
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- Adult, Aged, Aged, 80 and over, Asian People genetics, Female, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Incidence, Karyotype, Lymphoma, Large B-Cell, Diffuse ethnology, Male, Middle Aged, Proto-Oncogene Proteins c-bcl-6, White People genetics, DNA-Binding Proteins genetics, Gene Rearrangement, Genes, myc, Lymphoma, Large B-Cell, Diffuse genetics
- Abstract
To study the similarities and differences of cytogenetic alterations in diffuse large B-cell lymphoma (DLBCL) between Asian and Caucasian patients, we compared the cytogenetic profiles of Chinese and American DLBCL cases by analyzing conventional karyotypes and select fluorescence in situ hybridization (FISH) findings. We used interphase FISH analyses to determine the incidence of the t(14;18) and BCL6 and MYC rearrangements. Immunohistochemical analysis was used to categorize the lymphomas into the germinal center B-cell-like (GCB) or non-GCB-DLBCL subtypes, according to the Hans algorithm. Our data suggested that Chinese patients had cytogenetic profiles for GCB-DLBCL that differed from those of their American counterparts; specifically, the Chinese GCB patients exhibited greater frequencies of BCL6 rearrangements and gains of 1q and 11q but lower incidence of the t(14;18). Non-GCB-DLBCL in both the Chinese and American patients was characterized by recurrent gains of 3/3q and 18/18q. The incidences of both BCL6 rearrangement and t(14;18) were similar in Chinese and American non-GCB-DLBCL cases., (Copyright © 2013 Elsevier Inc. All rights reserved.)
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- 2013
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27. Cytogenetic abnormalities in follicular dendritic cell sarcoma: report of two cases and literature review.
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Perry AM, Nelson M, Sanger WG, Bridge JA, and Greiner TC
- Subjects
- Adult, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Combined Modality Therapy, Dendritic Cell Sarcoma, Follicular metabolism, Dendritic Cell Sarcoma, Follicular pathology, Dendritic Cell Sarcoma, Follicular therapy, Dendritic Cells, Follicular metabolism, Disease-Free Survival, Female, Humans, Lung Neoplasms genetics, Lung Neoplasms metabolism, Lung Neoplasms secondary, Middle Aged, Neoplasm Recurrence, Local, Psychosurgery, Soft Tissue Neoplasms pathology, Treatment Outcome, Chromosome Aberrations, Dendritic Cell Sarcoma, Follicular genetics, Dendritic Cells, Follicular pathology, Lymph Nodes pathology, Soft Tissue Neoplasms genetics
- Abstract
Background: The identification of chromosomal abnormalities in many hematopoietic and mesenchymal neoplasms has contributed significantly to classification systems. Follicular dendritic cell (FDC) sarcoma is an intermediate-grade malignancy with morphological and immunophenotypic features of follicular dendritic cells. Available data on genetic changes in this neoplasm are limited, with only isolated case reports of cytogenetic abnormalities., Case Report: We reviewed histological, immunophenotypic and cytogenetic findings in two cases of FDC sarcoma. The two cases of FDC sarcoma, were observed in female patients, one was nodal and one extranodal and they exhibited relatively complex karyotypes, characterized by structural abnormalities and loss of multiple chromosomes. One patient had several disease recurrences. At the last follow-up both patients were alive with no residual disease., Conclusion: The cytogenetic findings in these two cases, coupled with the few previously described abnormal karyotypes, suggest that FDC sarcoma is cytogenetically diverse.
- Published
- 2013
28. Early onset, EBV(-) PTLD in pediatric liver-small bowel transplantation recipients: a spectrum of plasma cell neoplasms with favorable prognosis.
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Perry AM, Aoun P, Coulter DW, Sanger WG, Grant WJ, and Coccia PF
- Subjects
- Child, Child, Preschool, Fatal Outcome, Female, Gastrointestinal Diseases surgery, Herpesvirus 4, Human, Humans, Infant, Male, Multiple Myeloma therapy, Neoplasms, Plasma Cell therapy, Postoperative Complications therapy, Prognosis, Remission Induction, Transplantation, Homologous, Intestine, Small transplantation, Liver Transplantation adverse effects, Multiple Myeloma pathology, Neoplasms, Plasma Cell pathology, Postoperative Complications pathology
- Abstract
EBV(-) posttransplantation lymphoproliferative disorders (PTLDs) are rare compared with EBV(+) PTLDs, occur later after transplantation, and have a poor response to treatment. Few studies have reported EBV(-) PTLD in pediatric solid-organ transplantation recipients. We describe 5 cases of EBV(-) PTLD in recipients of combined liver and small bowel allografts ranging in age from 16 months to 7 years. EBV(-) PTLD developed 9-22 months (median, 15) after transplantation. Morphologically, the lesions ranged from atypical plasma cell hyperplasia (a term not currently included in the World Health Organization classification) to plasmacytoma like. In all cases, in situ hybridization for EBV was negative, and molecular studies demonstrated clonal IgH gene rearrangements. Protein electrophoresis showed multiple clonal paraproteins in 4 of 5 cases. In 2 cases with a donor-recipient sex mismatch, FISH cytogenetics demonstrated that the plasma cells were of mixed donor/recipient origin. One patient died before therapy. Four patients were treated with high-dose dexamethasone, and 1 patient subsequently required thalidomide. All 4 remain in remission 75-128 months (median, 86) after diagnosis. In contrast to reports of EBV(-) PTLD in adults, these plasma cell lesions occurred early after transplantation and resolved completely after minimal treatment.
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- 2013
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29. Immunohistochemical and molecular cytogenetic evaluation of potential targets for tyrosine kinase inhibitors in Langerhans cell histiocytosis.
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Caponetti GC, Miranda RN, Althof PA, Dobesh RC, Sanger WG, Medeiros LJ, Greiner TC, and Weisenburger DD
- Subjects
- Adolescent, Adult, Antigens, CD1 metabolism, Child, Child, Preschool, Cytogenetics, Female, Histiocytosis, Langerhans-Cell genetics, Histiocytosis, Langerhans-Cell metabolism, Humans, Immunohistochemistry, Infant, Male, Middle Aged, Molecular Targeted Therapy, Receptors, Platelet-Derived Growth Factor genetics, S100 Proteins metabolism, Histiocytosis, Langerhans-Cell drug therapy, Protein Kinase Inhibitors therapeutic use, Protein-Tyrosine Kinases antagonists & inhibitors, Proto-Oncogene Proteins c-kit metabolism, Receptors, Platelet-Derived Growth Factor metabolism
- Abstract
Langerhans cell histiocytosis is a rare disorder of Langerhans cells, a component of the dendritic cell system, with an unknown pathogenesis. Conventional therapy for patients with Langerhans cell histiocytosis is usually effective, but some patients are refractory to treatment or develop toxicity. Thus, there is a need for innovative therapies. Recently, some cases of Langerhans cell histiocytosis were reported to express platelet-derived growth factor receptors α and β or c-KIT by immunohistochemistry, and some of these patients had a clinical response to imatinib mesylate. Other hematologic disorders with PDGFRα or PDGFRβ gene rearrangements also have responded to imatinib mesylate. The aim of this study was to evaluate immunohistochemical and molecular markers in Langerhans cell histiocytosis that would identify cases for possible treatment with tyrosine kinase inhibitors. We investigated formalin-fixed, paraffin-embedded tissue sections from 14 cases of Langerhans cell histiocytosis. As controls, we included cases of inflammatory dermatitis (n = 5) and dermatopathic lymphadenitis (n = 7). We performed immunohistochemistry for S100, CD1a, c-KIT, and platelet-derived growth factor receptors α and β. Fluorescence in situ hybridization analysis to detect rearrangements of the PDGFRα or PDGFRβ genes was also performed. Four (28.5%) of 14 cases of Langerhans cell histiocytosis were positive for platelet-derived growth factor receptor α, whereas absent/weak expression was seen in 10 cases and all controls. All cases were negative for platelet-derived growth factor receptor β and c-KIT. The fluorescence in situ hybridization studies were also negative in all 8 cases with adequate quality DNA. Our findings suggest that a subset of cases of Langerhans cell histiocytosis may be treated with tyrosine kinase inhibitors due to the expression of platelet-derived growth factor receptor α. Clinical trials that evaluate the use of tyrosine kinase inhibitors in Langerhans cell histiocytosis seem warranted and should evaluate these markers., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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30. A novel t(6;13)(q15;q34) translocation in a giant cell reparative granuloma (solid aneurysmal bone cyst).
- Author
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Pan Z, Sanger WG, Bridge JA, Hunter WJ, Siegal GP, and Wei S
- Subjects
- Abnormal Karyotype, Bone Cysts, Aneurysmal pathology, Bone Diseases pathology, Fingers pathology, Granuloma, Giant Cell pathology, Humans, Male, Middle Aged, Translocation, Genetic, Bone Cysts, Aneurysmal genetics, Bone Diseases genetics, Chromosomes, Human, Pair 13 genetics, Chromosomes, Human, Pair 6 genetics, Granuloma, Giant Cell genetics
- Abstract
Aneurysmal bone cyst is a rapidly growing and locally aggressive lesion that commonly affects children and young adults. Initially regarded as a reactive process, primary aneurysmal bone cyst is now widely accepted as a neoplasm owing to recent findings of recurrent clonal chromosomal alterations, mostly t(16;17)(q22;p13). However, other infrequent chromosomal rearrangements have also been reported. Giant cell reparative granuloma, previously regarded as a nonneoplastic process and histologically indistinguishable from the solid variant of aneurysmal bone cyst, is frequently seen in the gnathic bones and the short tubular bones of the hands and feet. Here we present such a case of giant cell reparative granuloma (solid aneurysmal bone cyst) in the finger of a 63-year-old white man. Cytogenetic analysis revealed a novel alteration involving a reciprocal translocation between 6q and 13q, with a karyotype of 46,XY,t(6;13)(q15;q34),del(20)(q13.1)., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
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31. Characterization of six novel patients with MECP2 duplications due to unbalanced rearrangements of the X chromosome.
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Sanmann JN, Bishay DL, Starr LJ, Bell CA, Pickering DL, Stevens JM, Kahler SG, Olney AH, Schaefer GB, and Sanger WG
- Subjects
- Abnormalities, Multiple diagnosis, Abnormalities, Multiple genetics, Child, Child, Preschool, Developmental Disabilities diagnosis, Developmental Disabilities genetics, Humans, Intellectual Disability diagnosis, Intellectual Disability genetics, Male, Chromosomes, Human, X, Gene Duplication, Methyl-CpG-Binding Protein 2 genetics, Translocation, Genetic
- Abstract
Males with duplication of the Xq28 region, including methyl CpG-binding protein 2 (MECP2), exhibit a characteristic phenotype, including developmental delay, intellectual disability, limited or absent speech, limited or absent ambulation, and recurrent respiratory infections. We report six males with MECP2 duplications identified using array comparative genomic hybridization. The minimal sizes of these duplications range from ∼0.08 to 14.13 Mb, which, to the best of our knowledge, are respectively the smallest and largest minimal size duplications molecularly characterized to date. Adjunct metaphase fluorescence in situ hybridization analysis further classified these duplications as tandem or as products of complex chromosomal rearrangements. Specifically, one complex rearrangement was described as a der(12)t(X;12)(q28;q24.33), which is the first report of a translocation involving MECP2 on Xq and chromosome 12. The other complex rearrangement was described as a rec(X)dup(Xq)inv(X)(p22.32q28)mat. Synthesis of the dysmorphic features identified in individuals with rec(X) chromosomes, including deletions in the pseudoautosomal region 1 (PAR1) at Xp22.33/Yp11.3 and duplications of the distal Xq region including MECP2, revealed a high prevalence of undescended testes (7/8) and micropenis (3/8) in this cohort. Given that micropenis is rare in the general population, but present in 38% of individuals in this cohort, a dosage anomaly at one or both loci may be a significant risk factor for this condition. Therefore, we recommend microarray testing for patients with unexplained micropenis, particularly when accompanied by other phenotypic anomalies., (Copyright © 2012 Wiley Periodicals, Inc.)
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- 2012
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32. Algorithmic approach for methyl-CpG binding protein 2 (MECP2) gene testing in patients with neurodevelopmental disabilities.
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Sanmann JN, Schaefer GB, Buehler BA, and Sanger WG
- Subjects
- Brain Diseases complications, Chromosomes, Human, Pair 15 genetics, DNA Mutational Analysis, Developmental Disabilities complications, Exons genetics, Female, Humans, Male, Sex Factors, Algorithms, Brain Diseases genetics, Developmental Disabilities genetics, Methyl-CpG-Binding Protein 2 genetics, Mutation genetics
- Abstract
Methyl-CpG binding protein 2 gene (MECP2) testing is indicated for patients with numerous clinical presentations, including Rett syndrome (classic and atypical), unexplained neonatal encephalopathy, Angelman syndrome, nonspecific mental retardation, autism (females), and an X-linked family history of developmental delay. Because of this complexity, a gender-specific approach for comprehensive MECP2 gene testing is described. Briefly, sequencing of exons 1 to 4 of MECP2 is recommended for patients with a Rett syndrome phenotype, unexplained neonatal encephalopathy, an Angelman syndrome phenotype (with negative 15q11-13 analysis), nonspecific mental retardation, or autism (females). Additional testing for large-scale MECP2 deletions is recommended for patients with Rett syndrome or Angelman syndrome phenotypes (with negative 15q11-13 analysis) following negative sequencing. Alternatively, testing for large-scale MECP2 duplications is recommended for males presenting with mental retardation, an X-linked family history of developmental delay, and a significant proportion of previously described clinical features (particularly a history of recurrent respiratory infections).
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- 2012
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33. Primary follicular lymphoma of the testis in children and adolescents.
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Lones MA, Raphael M, McCarthy K, Wotherspoon A, Terrier-Lacombe MJ, Ramsay AD, Maclennan K, Cairo MS, Gerrard M, Michon J, Patte C, Pinkerton R, Sender L, Auperin A, Sposto R, Weston C, Heerema NA, Sanger WG, von Allmen D, and Perkins SL
- Subjects
- Adolescent, Child, Child, Preschool, Humans, Lymphoma, Follicular mortality, Lymphoma, Follicular pathology, Male, Testicular Neoplasms mortality, Testicular Neoplasms pathology, Lymphoma, Follicular therapy, Testicular Neoplasms therapy
- Abstract
This study reports 6 cases of primary follicular lymphoma of the testis (PFLT) in children and adolescents correlated with clinical presentation, pathologic features, treatment, and outcome. All 6 patients (age, 3 to 16 y; median, 4 y) had PFLT grade 3 with disease limited to the testis, completely resected and treated with 2 courses of chemotherapy (cyclophosphamide, vincristine, prednisone, doxorubicin). Event-free survival was 100% (follow-up: median, 73 mo; mean, 53 mo; range, 6 to 96 mo). In conclusion, clinical outcome in children and adolescents with PFLT is excellent with treatment including complete surgical resection and 2 courses of cyclophosphamide, vincristine, prednisone, doxorubicin.
- Published
- 2012
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34. Lymphoma cytogenetics.
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Dave BJ, Nelson M, and Sanger WG
- Subjects
- Chromosome Aberrations, Disease Progression, Humans, In Situ Hybridization, Fluorescence, Lymphoma pathology, Oligonucleotide Array Sequence Analysis, Prognosis, Cytogenetics methods, Lymphoma genetics
- Abstract
Lymphomas are a heterogeneous group of neoplasms with distinct morphologic, immunologic, and cytogenetic characteristics. Overlapping morphologic and immunophenotypic features often makes accurate diagnosis difficult. Cytogenetics helps simplify the diagnostic complexities presented in transforming and progressive lymphoid malignancies. Genetic studies using technical advances such as fluorescence in situ hybridization and the newer approaches of array comparative genomic hybridization and gene expression profiling play a critical and often defining role in the diagnosis, progression, prognosis, and therapeutic stratification. This article reviews characteristic cytogenetic abnormalities in specific subtypes of lymphomas at diagnosis, disease progression, and prognosis.
- Published
- 2011
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35. Genome wide copy number analysis of paediatric Burkitt lymphoma using formalin-fixed tissues reveals a subset with gain of chromosome 13q and corresponding miRNA over expression.
- Author
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Schiffman JD, Lorimer PD, Rodic V, Jahromi MS, Downie JM, Bayerl MG, Sanmann JN, Althof PA, Sanger WG, Barnette P, Perkins SL, and Miles RR
- Subjects
- Adolescent, Burkitt Lymphoma pathology, Child, Child, Preschool, DNA Copy Number Variations, Female, Formaldehyde, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, MicroRNAs genetics, Paraffin Embedding, Tissue Fixation, Burkitt Lymphoma genetics, Chromosomes, Human, Pair 13, MicroRNAs biosynthesis
- Abstract
The majority of paediatric Burkitt lymphoma (pBL) patients that relapse will die of disease, but markers for this high-risk subset are unknown. MYC translocations characterize pBL, but additional genetic changes may relate to prognosis and serve as potential biomarkers. We utilized a molecular inversion probe single nucleotide polymorphism assay to perform high resolution, genome-wide copy number analysis on archival formalin-fixed, paraffin-embedded pBL and germline tissues. We identified copy number abnormalities (CNAs) in 18/28 patients (64%) with a total of 62 CNAs that included 32 gains and 30 copy number losses. We identified seven recurrent CNAs including 1q gain (7/28, 25%), 13q gain (3/28, 11%), and 17p loss (4/28, 14%). The minimum common amplified region on 13q was at 13q31 and included the MIR17HG (MIR17-92) locus. Samples with this gain had higher levels of MIR17 RNA and showed a tendency for early relapse. Tumour-specific uniparental disomy was identified in 32% of cases and usually was recurrent. These results demonstrate that high-resolution copy number analysis can be performed on archival lymphoma tissue specimens, which has significance for the study of rare diseases., (© 2011 Blackwell Publishing Ltd.)
- Published
- 2011
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36. Large contiguous gene deletions in Sjögren-Larsson syndrome.
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Engelstad H, Carney G, S'aulis D, Rise J, Sanger WG, Rudd MK, Richard G, Carr CW, Abdul-Rahman OA, and Rizzo WB
- Subjects
- Aldehyde Oxidoreductases metabolism, Base Sequence, Comparative Genomic Hybridization, DNA Primers genetics, Female, Genotype, Humans, In Situ Hybridization, Fluorescence, Infant, Microarray Analysis, Molecular Sequence Data, Mutation, Missense genetics, Pedigree, Polymerase Chain Reaction, Sequence Analysis, DNA, Sjogren-Larsson Syndrome pathology, Young Adult, Aldehyde Oxidoreductases genetics, Chromosomes, Human, Pair 17 genetics, Gene Deletion, Sjogren-Larsson Syndrome genetics
- Abstract
Sjögren-Larsson syndrome (SLS) is an autosomal recessive disorder characterized by ichthyosis, mental retardation, spasticity and mutations in the ALDH3A2 gene for fatty aldehyde dehydrogenase, an enzyme that catalyzes the oxidation of fatty aldehyde to fatty acid. More than 70 mutations have been identified in SLS patients, including small deletions or insertions, missense mutations, splicing defects and complex nucleotide changes. We now describe 2 SLS patients whose disease is caused by large contiguous gene deletions of the ALDH3A2 locus on 17p11.2. The deletions were defined using long distance inverse PCR and microarray-based comparative genomic hybridization. A 24-year-old SLS female was homozygous for a 352-kb deletion involving ALDH3A2 and 4 contiguous genes including ALDH3A1, which codes for the major soluble protein in cornea. Although lacking corneal disease, she showed severe symptoms of SLS with uncommon deterioration in oral motor function and loss of ambulation. The other 19-month-old female patient was a compound heterozygote for a 1.44-Mb contiguous gene deletion and a missense mutation (c.407C>T, P136L) in ALDH3A2. These studies suggest that large gene deletions may account for up to 5% of the mutant alleles in SLS. Geneticists should consider the possibility of compound heterozygosity for large deletions in patients with SLS and other inborn errors of metabolism, which has implications for carrier testing and prenatal diagnosis., (Copyright © 2011 Elsevier Inc. All rights reserved.)
- Published
- 2011
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37. An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities.
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Kaminsky EB, Kaul V, Paschall J, Church DM, Bunke B, Kunig D, Moreno-De-Luca D, Moreno-De-Luca A, Mulle JG, Warren ST, Richard G, Compton JG, Fuller AE, Gliem TJ, Huang S, Collinson MN, Beal SJ, Ackley T, Pickering DL, Golden DM, Aston E, Whitby H, Shetty S, Rossi MR, Rudd MK, South ST, Brothman AR, Sanger WG, Iyer RK, Crolla JA, Thorland EC, Aradhya S, Ledbetter DH, and Martin CL
- Subjects
- Cytogenetic Analysis, Gene Dosage, Genome, Human, Humans, DNA Copy Number Variations, Developmental Disabilities genetics, Evidence-Based Medicine methods, Intellectual Disability genetics
- Abstract
Purpose: Copy number variants have emerged as a major cause of human disease such as autism and intellectual disabilities. Because copy number variants are common in normal individuals, determining the functional and clinical significance of rare copy number variants in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large copy number variant datasets generated through routine patient care., Methods: A consortium of diagnostic laboratories was established (the International Standards for Cytogenomic Arrays consortium) to share copy number variant and phenotypic data in a central, public database. We present the largest copy number variant case-control study to date comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 copy number variant regions., Results: Compared with controls, 14 deletions and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic., Conclusion: Given the rapid expansion of clinical chromosomal microarray analysis testing, very large datasets will be available to determine the functional significance of increasingly rare copy number variants. This data will provide an evidence-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.
- Published
- 2011
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38. Molecular characteristics of mantle cell lymphoma presenting with clonal plasma cell component.
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Visco C, Hoeller S, Malik JT, Xu-Monette ZY, Wiggins ML, Liu J, Sanger WG, Liu Z, Chang J, Ranheim EA, Gradowski JF, Serrano S, Wang HY, Liu Q, Dave S, Olsen B, Gascoyne RD, Campo E, Swerdlow SH, Chan WC, Tzankov A, and Young KH
- Subjects
- Aged, Aged, 80 and over, Biomarkers, Tumor metabolism, Clone Cells, DNA, Neoplasm analysis, Female, Humans, Immunoenzyme Techniques, Immunoglobulin Heavy Chains genetics, Immunophenotyping, In Situ Hybridization, Fluorescence, Lymphoid Tissue metabolism, Lymphoid Tissue pathology, Lymphoma, Mantle-Cell metabolism, Lymphoma, Mantle-Cell pathology, Male, Microdissection, Middle Aged, Plasma Cells metabolism, Polymorphism, Restriction Fragment Length, Chromosomes, Human, Pair 11, Chromosomes, Human, Pair 14, Lymphoma, Mantle-Cell genetics, Plasma Cells pathology, Translocation, Genetic genetics
- Abstract
The normal counterparts of mantle cell lymphoma (MCL) are naive, quiescent B cells that have not been processed through the germinal center (GC). For this reason, although lymphomas arising from GC or post-GC B cells often exhibit plasmacytic differentiation, MCL rarely presents with plasmacytic features. Seven cases of MCL with a monotypic plasma cell (PC) population were collected from 6 centers and were studied by immunohistochemistry, fluorescence immunophenotyping and interphase cytogenetics as a tool for the investigation of neoplasms analysis, capillary gel electrophoresis, and restriction fragment length polymorphism of immunoglobulin heavy chain analysis of microdissections of each of the MCL and PC populations to assess their clonal relationship. The clinical presentation was rather unusual compared with typical MCL, with 2 cases arising from the extranodal soft tissues of the head. All MCL cases were morphologically and immunohistochemically typical, bearing the t(11;14)(q13;q32). In all cases, the PC population was clonal. In 5 of the 7 cases, the MCL and PC clones showed identical restriction fragments, indicating a common clonal origin of the neoplastic population. The 2 cases with clonal diversity denoted the coexistence of 2 different tumors in a composite lymphoma/PC neoplasm. Our findings suggest that MCL can present with a PC component that is often clonally related to the lymphoma, representing a rare but unique biological variant of this tumor.
- Published
- 2011
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39. Rapid aneuploidy screening with fluorescence in-situ hybridisation: is it a sufficiently robust stand-alone test for prenatal diagnosis?
- Author
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Lim AS, Lim TH, Hess MM, Kee SK, Lau YY, Gilbert R, Hempel TE, Anderson KJ, Zaleski DH, Tien SL, Chia P, Subramaniam R, Tan HK, Tan AS, and Sanger WG
- Subjects
- Adult, Female, Humans, Maternal Age, Pregnancy, Retrospective Studies, Aneuploidy, In Situ Hybridization, Fluorescence methods, Prenatal Diagnosis methods
- Abstract
Objectives: To assess the clinical utility of fluorescence in-situ hybridisation with chromosomes 13, 18, 21, X and Y as a stand-alone test in detecting chromosomal abnormalities, and the types of chromosomal abnormalities missed., Design: Retrospective analysis., Setting: A restructured Government hospital in Singapore and an academic hospital in the United States., Participants: Cytogenetic data of prenatal specimens and results of fluorescence in-situ hybridisation of 5883 patients performed between January 2000 and August 2007 were reviewed., Results: Fluorescence in-situ hybridisation detected 558 (9.5%) patients with chromosomal abnormalities. Abnormal ultrasounds (70%) and maternal serum screens (21%) were the most indicative of chromosomal abnormalities. When comparing fluorescence in-situ hybridisation data with karyotype results for the five chromosomes of interest, the sensitivity and specificity were 99.3% and 99.9%, respectively. When comparing fluorescence in-situ hybridisation data with karyotype results for all chromosomes, the sensitivity decreased to 86.8%, whereas the specificity remained at 99.9%. Of 643 cases with karyotype abnormalities, 85 were fluorescence in-situ hybridisation-negative (false negative rate, 13.2%), which included structural rearrangements, chromosome mosaicism, and other trisomies. Despite abnormal ultrasound indications, fluorescence in-situ hybridisation missed 32 cases which included structural rearrangements, mosaicisms, and other trisomies., Conclusion: This study does not support fluorescence in-situ hybridisation as a stand-alone test. Institutions supporting fluorescence in-situ hybridisation as a stand-alone test must seriously consider the risks of a missed diagnosis.
- Published
- 2010
40. Array comparative genomic hybridization findings in a cohort referred for an autism evaluation.
- Author
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Schaefer GB, Starr L, Pickering D, Skar G, Dehaai K, and Sanger WG
- Subjects
- Child, Child Development Disorders, Pervasive complications, Cohort Studies, Female, Genotype, Humans, Male, Child Development Disorders, Pervasive diagnosis, Child Development Disorders, Pervasive genetics, Comparative Genomic Hybridization methods, Genetic Predisposition to Disease genetics
- Abstract
The development and refinement of array comparative genomic hybridization has led to expanded applications as a diagnostic tool. Recent reports suggest a high diagnostic yield for array comparative genomic hybridization in autism spectrum disorders. The objective of this study was to determine the diagnostic yield in array comparative genomic hybridization for autism at the University of Nebraska Medical Center. The authors report the diagnostic yield of array comparative genomic hybridization in 89 samples with a primary indication of autism. Clinical information was reviewed for 89 identified cases. Twenty-one cases were excluded because of ambiguous information regarding the diagnosis, a diagnosis other than autism, or abnormal karyotype. Of 68 cases referred for array comparative genomic hybridization testing with a primary indication of autism, 14 (21%) had abnormal findings. This study supports array comparative genomic hybridization in the etiologic evaluation of autism and elevation of array to a first tier diagnostic test.
- Published
- 2010
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41. Deletion 17q12 is a recurrent copy number variant that confers high risk of autism and schizophrenia.
- Author
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Moreno-De-Luca D, Mulle JG, Kaminsky EB, Sanders SJ, Myers SM, Adam MP, Pakula AT, Eisenhauer NJ, Uhas K, Weik L, Guy L, Care ME, Morel CF, Boni C, Salbert BA, Chandrareddy A, Demmer LA, Chow EW, Surti U, Aradhya S, Pickering DL, Golden DM, Sanger WG, Aston E, Brothman AR, Gliem TJ, Thorland EC, Ackley T, Iyer R, Huang S, Barber JC, Crolla JA, Warren ST, Martin CL, and Ledbetter DH
- Subjects
- Child, Child Development Disorders, Pervasive genetics, Child, Preschool, Facies, Female, Humans, Male, Phenotype, Chromosomes, Human, Pair 17, DNA Copy Number Variations, Schizophrenia genetics, Sequence Deletion
- Abstract
Autism spectrum disorders (ASD) and schizophrenia are neurodevelopmental disorders for which recent evidence indicates an important etiologic role for rare copy number variants (CNVs) and suggests common genetic mechanisms. We performed cytogenomic array analysis in a discovery sample of patients with neurodevelopmental disorders referred for clinical testing. We detected a recurrent 1.4 Mb deletion at 17q12, which harbors HNF1B, the gene responsible for renal cysts and diabetes syndrome (RCAD), in 18/15,749 patients, including several with ASD, but 0/4,519 controls. We identified additional shared phenotypic features among nine patients available for clinical assessment, including macrocephaly, characteristic facial features, renal anomalies, and neurocognitive impairments. In a large follow-up sample, the same deletion was identified in 2/1,182 ASD/neurocognitive impairment and in 4/6,340 schizophrenia patients, but in 0/47,929 controls (corrected p = 7.37 × 10⁻⁵). These data demonstrate that deletion 17q12 is a recurrent, pathogenic CNV that confers a very high risk for ASD and schizophrenia and show that one or more of the 15 genes in the deleted interval is dosage sensitive and essential for normal brain development and function. In addition, the phenotypic features of patients with this CNV are consistent with a contiguous gene syndrome that extends beyond RCAD, which is caused by HNF1B mutations only., (Copyright © 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
- Published
- 2010
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42. 18q22.3 --> 18q23 deletion syndrome and cleft palate.
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Eudy JD, Pickering DL, Lutz R, Platt K, Dave BJ, Olney AH, and Sanger WG
- Subjects
- Child, Comparative Genomic Hybridization, Female, Humans, Male, Pedigree, Syndrome, Chromosome Deletion, Chromosomes, Human, Pair 18 genetics, Cleft Palate genetics
- Published
- 2010
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43. An increased frequency of 13q deletions detected by fluorescence in situ hybridization and its impact on survival in children and adolescents with Burkitt lymphoma: results from the Children's Oncology Group study CCG-5961.
- Author
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Nelson M, Perkins SL, Dave BJ, Coccia PF, Bridge JA, Lyden ER, Heerema NA, Lones MA, Harrison L, Cairo MS, and Sanger WG
- Subjects
- Adolescent, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Burkitt Lymphoma drug therapy, Burkitt Lymphoma pathology, Child, Child, Preschool, Epidemiologic Methods, Female, Humans, In Situ Hybridization, Fluorescence, Infant, Male, Neoplasm Staging, Prognosis, Treatment Outcome, Young Adult, Burkitt Lymphoma genetics, Chromosome Deletion, Chromosomes, Human, Pair 13 genetics
- Abstract
Burkitt lymphoma (BL), an aggressive B-cell malignancy, is often curable with short intensive treatment regiments. Nearly all BLs contain rearrangements of the MYC/8q24 region; however, recent cytogenetic studies suggest that certain secondary chromosomal aberrations in BL correlate with an adverse prognosis. In this multi-centre study, the frequency and impact on clinical outcome of del(13q) and +7 in addition to MYC rearrangements as detected by fluorescence in situ hybridization (FISH) in children and adolescents with intermediate and high-risk BL registered on Children's Cancer Group study CCG-5961 were investigated. Analysis with 13q14.3 and 13q34 loci specific probes demonstrated deletions of 13q in 38/90 (42%) cases. The loss of either 13q14.3 or 13q34 alone occurred in 14% and 8% respectively, while 20% exhibited loss of both regions. Gain of chromosome 7 was observed in 7/68 (10%) cases and MYC rearrangements were detected in 84/90 (93%). Prognostic analysis controlling for known risk factors demonstrated that patients exhibiting loss of 13q, particularly 13q14.3, had a significant decrease in 5-year overall survival (77% vs. 95%, P = 0.012). These observations indicate that del(13q) occurs in childhood BL at frequencies higher than previously detected by classical cytogenetics and underscores the importance of molecular cytogenetics in risk stratification.
- Published
- 2010
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44. Variability in interpreting and reporting copy number changes detected by array-based technology in clinical laboratories.
- Author
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Tsuchiya KD, Shaffer LG, Aradhya S, Gastier-Foster JM, Patel A, Rudd MK, Biggerstaff JS, Sanger WG, Schwartz S, Tepperberg JH, Thorland EC, Torchia BA, and Brothman AR
- Subjects
- Chromosomes, Artificial, Bacterial genetics, Clinical Laboratory Techniques standards, Clinical Laboratory Techniques statistics & numerical data, Comparative Genomic Hybridization methods, Comparative Genomic Hybridization statistics & numerical data, Gene Expression Profiling methods, Gene Expression Profiling standards, Gene Expression Profiling statistics & numerical data, Humans, In Situ Hybridization, Fluorescence methods, In Situ Hybridization, Fluorescence statistics & numerical data, Observer Variation, Oligonucleotide Array Sequence Analysis methods, Oligonucleotide Array Sequence Analysis statistics & numerical data, Research Personnel standards, Surveys and Questionnaires, Comparative Genomic Hybridization standards, Gene Dosage, In Situ Hybridization, Fluorescence standards, Oligonucleotide Array Sequence Analysis standards
- Abstract
Purpose: : The purpose of this study was to assess the variability in interpretation and reporting of copy number changes that are detected by array-based technology in the clinical laboratory., Methods: : Thirteen different copy number changes, detected by array comparative genomic hybridization, that have not been associated with an abnormal phenotype in the literature were evaluated by directors from 11 different clinical laboratories to determine how they would interpret and report the findings., Results: : For none of the thirteen copy number changes was there complete agreement in the interpretation of the clinical significance of the deletion or duplication. For some cases, the interpretations ranged from normal to abnormal., Conclusion: : There is a need for more specific guidelines for interpreting and reporting copy number changes detected by array-based technology to clearly and more consistently communicate the clinical significance of these findings to ordering providers.
- Published
- 2009
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45. Inherited 14q duplication and 21q deletion: a rare adjacent-2 segregation in multiple family members.
- Author
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Dave BJ, Olney AH, Zaleski DH, Pickering DL, Becker TA, Chipman HE, and Sanger WG
- Subjects
- Abnormalities, Multiple genetics, Adult, Chromosome Deletion, Family, Female, Gene Duplication, Humans, Infant, Male, Pedigree, Chromosome Aberrations, Chromosome Disorders genetics, Chromosome Segregation genetics, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 21
- Abstract
We present a family with multiple carriers of a subtle balanced translocation t(14;21)(q21.2;q21.2) and three patients with a resultant adjacent-2 malsegregation containing a +der(14)t(14;21)(q21.2;q21.2),-21 in their chromosome complement. The initial study was performed when a 2-month-old female was referred to genetics clinic for evaluation of developmental delay, growth retardation, and failure to thrive. Physical findings included prominent eyes, micrognathia, prominent and simple external ears, camptodactyly, contractures of the wrists, ankles, and hips, hypoplasia of the corpus callosum, prominent atria and occipital horns, cerebellopontine hypoplasia; and small atrial septal defect. High resolution chromosomes showed an extra band on the proximal 21q and fluorescence in situ hybridization (FISH) demonstrated only one signal for the centromere of 21. Karyotypes of the parents and grandparents revealed that the mother and maternal grandfather were carriers of a balanced translocation, and the propositus contained an unbalanced chromosome complement with partial duplication of proximal 14q and partial deletion of proximal 21q. Investigations performed on an institutionalized maternal aunt revealed identical karyotypic abnormalities as in the propositus. More recently, array comparative genomic hybridization (aCGH) on a subsequent child with multiple congenital anomalies further out in the extended family allowed for more accurate identification of the breakpoints. Our investigation includes analysis on a total of 11 family members spanning three generations. Among those investigated, there were no living members with other possible consequential unbalanced translocations or with adjacent-2 segregation resulting in -14,+der(21). Chromosome rearrangements require FISH and aCGH studies for accurate identification and elucidation of the abnormality and breakpoints.
- Published
- 2009
- Full Text
- View/download PDF
46. t(14;18)-negative follicular lymphomas are associated with a high frequency of BCL6 rearrangement at the alternative breakpoint region.
- Author
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Gu K, Fu K, Jain S, Liu Z, Iqbal J, Li M, Sanger WG, Weisenburger DD, Greiner TC, Aoun P, Dave BJ, and Chan WC
- Subjects
- Adult, Aged, Aged, 80 and over, Chromosome Breakage, Chromosomes, Human, Pair 14 genetics, Chromosomes, Human, Pair 18 genetics, Female, Humans, In Situ Hybridization, Fluorescence, Lymphoma, Large B-Cell, Diffuse genetics, Male, Middle Aged, Proto-Oncogene Proteins c-bcl-6, Translocation, Genetic genetics, DNA-Binding Proteins genetics, Gene Rearrangement, Lymphoma, Follicular genetics
- Abstract
A frequent chromosomal translocation in mature B-cell non-Hodgkin lymphoma affects band 3q27 and results in the deregulation of the B-cell lymphoma 6 (BCL6) gene. Two breakpoint clusters have been described thus far, the major breakpoint region (MBR) and an alternative breakpoint region (ABR) that is located 245-285 kb 5' to BCL6. Translocation at the MBR predominates in diffuse large B-cell lymphoma, whereas translocation at the ABR is reported to be frequently associated with grade 3B follicular lymphoma. However, translocation at the ABR has not been studied in a large series of follicular lymphomas, particularly t(14;18)-negative follicular lymphomas. Therefore, we studied BLC6 rearrangements at the MBR and ABR by using break-apart fluorescence in situ hybridization (FISH) probes in 142 cases of follicular lymphomas, including 63 t(14;18)-negative and 79 t(14;18)-positive cases. Conventional cytogenetic (karyotype) analysis was also performed in 58 of the 63 t(14;18)-negative cases. BCL6 rearrangement was found in 26% of t(14;18)-negative and 19% of t(14;18)-positive follicular lymphoma. t(14;18)-negative cases showed a high frequency of rearrangement at the ABR (12%) with an ABR/MBR ratio of 0.86, compared with only 5% with an ABR/MBR ratio of 0.36 in the t(14;18)-positive cases. BCL6 rearrangements were found in all grades of follicular lymphoma but were most frequent in grade 3 t(14;18)-negative follicular lymphoma (60%). FISH analysis had a higher sensitivity for detecting BCL6 rearrangements than conventional cytogenetics. In conclusion, BCL6 rearrangements occur at a similar frequency in t(14;18)-negative follicular lymphoma and diffuse large B-cell lymphoma. However, t(14;18)-negative follicular lymphoma appears to have a higher frequency of rearrangement at the ABR compared with t(14;18)-positive follicular lymphoma and diffuse large B-cell lymphoma. Therefore, it is important to perform FISH analysis with ABR to determine possible involvement of BCL6 rearrangement in follicular lymphoma, especially in t(14;18)-negative cases.
- Published
- 2009
- Full Text
- View/download PDF
47. Mantle cell lymphoma with flow cytometric evidence of clonal plasmacytic differentiation: a case report.
- Author
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Naushad H, Choi WW, Page CJ, Sanger WG, Weisenburger DD, and Aoun P
- Subjects
- Aged, Clone Cells pathology, Flow Cytometry, Humans, Immunohistochemistry, Male, Sensitivity and Specificity, Cell Differentiation, Lymphoma, Mantle-Cell pathology, Plasma Cells pathology
- Abstract
Background: Plasmacytic differentiation in mantle cell lymphoma (MCL) occurs rarely. However, no flow cytometric studies that demonstrate plasmacytic (PC) differentiation in MCL have been reported. Herein, we report a case of MCL with PC differentiation identified by flow cytometry., Methods: Morphologic review was performed by hematoxylin and eosin (H&E) stained sections from paraffin-embedded lymph node, colon and bone marrow specimens, and Wright-Geimsa stained bone marrow aspirate smears and touch imprints. Immunohistochemical stains using antibodies against CD3, CD5, CD20, and cyclin-D1, and in-situ hybridization for kappa and lambda light chains were reviewed. Multicolor flow cytometry analysis was performed on the bone marrow aspirate with monoclonal antibodies to CD3, CD4, CD5, CD8, CD14, CD19, CD20, CD23, CD38, CD45, CD56, CD138, and kappa and lambda light chains. FISH analysis for t(11;14)(q13;q32) was performed on interphase cells., Results: The neoplastic cells had the cytologic features of MCL with nodal, bone marrow, and colonic involvement. In-situ hybridization for kappa and lambda light chains demonstrated clonal plasma cells in the lymph node and bone marrow biopsies. In addition, flow cytometric studies of the bone marrow aspirate showed three populations of neoplastic cells: a clonal B-cell population with typical MCL phenotype, a similar B-cell population in transition to plasma cells, and a clonal plasma cell population. The plasma cells retained CD5 expression and had the same light chain restriction as the clonal B-cells., Conclusions: Multi-parameter flow cytometry can be useful in demonstrating clonal PC differentiation in MCL and distinguishing from a concurrent but unrelated plasma cell dyscrasia., ((c) 2008 Clinical Cytometry Society.)
- Published
- 2009
- Full Text
- View/download PDF
48. Clonal evolution in t(14;18)-positive follicular lymphoma, evidence for multiple common pathways, and frequent parallel clonal evolution.
- Author
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d'Amore F, Chan E, Iqbal J, Geng H, Young K, Xiao L, Hess MM, Sanger WG, Smith L, Wiuf C, Hagberg O, Fu K, Chan WC, and Dave BJ
- Subjects
- Chromosome Aberrations, Clone Cells, Disease Progression, Humans, Kaplan-Meier Estimate, Karyotyping, Lymphoma, Follicular mortality, Translocation, Genetic, Chromosomes, Human, Pair 14, Chromosomes, Human, Pair 18, Lymphoma, Follicular genetics, Lymphoma, Follicular pathology
- Abstract
Purpose: Follicular lymphoma typically has acquired a t(14;18) translocation, but subsequent additional cytogenetic abnormalities contribute to disease progression. The main aims of the study are to (a) identify the frequency and temporal sequence of cytogenetic events in t(14;18)-positive follicular lymphoma, (b) determine if there are specific pathways in the evolution of follicular lymphoma, (c) determine the clonal divergence in cases with sequential biopsies or multiple clones from a single biopsy, and (d) determine the association of genetic imbalances with clinical outcome., Experimental Design: All cases with a histologically confirmed diagnosis of follicular lymphoma and cytogenetic analysis showing t(14;18)(q32;q21) were included. The karyotypes were reviewed and cytogenetic data were entered into a relational database for further computational analysis; 418 biopsies from 360 follicular lymphoma patients including 43 sequential biopsies were analyzed., Results: Of the cases with only one or two genomic imbalances, the most frequent chromosomal imbalances were +7, del(6q), +der(18)t(14;18), +18, and +X. These abnormalities were also among the most frequent ones encountered when all karyotypes were analyzed. Cytogenetically abnormal clones in the same (26%) and sequential biopsies (63%) often showed divergence of genetic alterations. Balanced translocations other than the t(14;18) were uncommon events, but chromosomal breaks involving 14q32, 18q21, 1p36, 1q21, 10q22, 10q24, and a large cluster at 6q occurred relatively frequently. del(6q), +5, +19, and +20 were associated with poorer overall survival, and del(17p) was associated with poorer event-free survival. Lower-grade tumors (1 and 2) were associated with fewer imbalances., Conclusion: Our analysis suggested that +der(18)t(14;18) may be an entry point to a distinct pathway of genetic evolution in follicular lymphoma. The other common early events appeared to provide multiple entry points, and they might cooperate in the pathogenesis and progression of the follicular lymphoma. Cytogenetically abnormal clones from same patients often showed divergence of genetic alterations, suggesting that parallel evolution from precursor clones are frequent events. This study provides the framework for further analysis of genetic pathways of tumor progression.
- Published
- 2008
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49. Genetic counseling for DAPK1 mutation in a chronic lymphocytic leukemia family.
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Lynch HT, Ferrara KM, Weisenburger DD, Sanger WG, Lynch JF, and Thomé SD
- Subjects
- Adult, Aged, Death-Associated Protein Kinases, Female, Humans, Male, Middle Aged, Apoptosis Regulatory Proteins genetics, Calcium-Calmodulin-Dependent Protein Kinases genetics, Genetic Counseling, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Mutation
- Abstract
Genetic counseling has become the clinical bedrock of hereditary cancer management. Countless advances in molecular genetics contributing to the identification of cancer-causing germline mutations have increased its importance. We report a unique genetic counseling experience involving a family with hereditary chronic lymphocytic leukemia and the cancer-causing mutation in the death-associated protein kinase 1 gene (DAPK1). This hereditary disorder currently lacks any preventive or curative interventions for mutation carriers. This family has been under our investigation for a decade, during which time genealogy, cancer of all anatomic sites, medical and pathology records, and, whenever possible, slides and tissue blocks were reviewed. Family attendance at three group-oriented family information service sessions provided intensive education about this disease. Blood and skin fibroblasts were obtained for molecular genetic studies of DNA leading to the discovery of the DAPK1 mutation in the family. Their intellectual and emotional reaction to its presence or absence in them was assessed. This family serves as a model for genetic counseling in disorders for which lifesaving intervention is not yet possible.
- Published
- 2008
- Full Text
- View/download PDF
50. Characterization of childhood precursor T-lymphoblastic lymphoma by immunophenotyping and fluorescent in situ hybridization: a report from the Children's Oncology Group.
- Author
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Smock KJ, Nelson M, Tripp SR, Sanger WG, Abromowitch M, Cairo MS, and Perkins SL
- Subjects
- Child, Humans, Immunohistochemistry, Immunophenotyping, In Situ Hybridization, Fluorescence, Medical Oncology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma immunology, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma classification, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology
- Abstract
Background: T-lymphoblastic lymphoma (T-LBL) accounts for 25-30% of childhood non-Hodgkin's lymphoma and is closely related to T-lymphoblastic leukemia (T-ALL). Recently, we demonstrated distinct differences in gene expression between childhood T-LBL and T-ALL, but molecular pathogenesis and relevant protein expression patterns in T-LBL remain poorly understood., Procedure: Children with T-LBL with disseminated disease were registered and treated on COG protocol 5971. Paraffin-embedded tumor tissue was obtained at diagnosis for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) studies. We determined the pattern and intensity of staining for c-Myc, Skp2, Mib-1, p53, TCL-1, bcl-2, and bcl-6 proteins by IHC and c-Myc, p53, bcl-2, bcl-6, and TCR alpha/delta molecular alterations by FISH in 22 pediatric T-LBL cases., Results: The majority of T-LBL samples expressed Mib-1 (59%) and c-Myc (77%) proteins in greater than 50% of the cells, but Skp2 (14%), p53 (14%), and bcl-2 (23%) expression was less common. FISH studies demonstrated 18% gains and 10% losses in c-Myc, 16% gains in p53, 12% gains and 6% losses in bcl-2, and 6% gains and 19% losses in bcl-6 with little direct correlation between the IHC and FISH studies., Conclusions: Childhood T-LBL is a highly proliferative tumor associated with enhanced expression of c-Myc protein, but without detectable c-Myc molecular alterations. FISH studies did not identify consistent etiologies of molecular dysregulation, and future studies with other molecular approaches may be required to elucidate the molecular pathogenesis of childhood T-LBL., ((c) 2008 Wiley-Liss, Inc.)
- Published
- 2008
- Full Text
- View/download PDF
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