74 results on '"Linlea Armstrong"'
Search Results
2. Impact of variation in practice in the prenatal reporting of variants of uncertain significance by commercial laboratories: Need for greater adherence to published guidelines
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Melissa Cornthwaite, Kelly Turner, Linlea Armstrong, Cornelius F. Boerkoel, Caitlin Chang, Anna Lehman, Sarah M. Nikkel, Millan S. Patel, Margot Van Allen, and Sylvie Langlois
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Fetus ,Pregnancy ,Exome Sequencing ,Humans ,Obstetrics and Gynecology ,Female ,Exome ,Genetic Testing ,General Medicine ,Laboratories ,Genetics (clinical) ,Retrospective Studies - Abstract
To evaluate the impact of implementing commercial whole exome sequencing (WES) and targeted gene panel testing in pregnancies with fetal anomalies.A retrospective chart review of 124 patients with sequencing performed by commercial laboratories.The diagnostic yield of WES and panel testing was 21.5% and 26%, respectively, based on likely pathogenic (LP) or pathogenic (P) variants. Forty-two percent of exomes and 32% of panels analysed had one or more variants of uncertain significance (VUS) reported. A multidisciplinary in-depth review of the fetal phenotype, disease phenotype, variant data, and, in some patients, additional prenatal or postnatal investigations increased the diagnostic yield by 5% for exome analysis and 6% for panel analysis.The diagnostic yield of WES and panel testing combined was 23% based on LP and P variants. Although the reporting of VUS contributed to a 5% increase in diagnostic yield for WES and 6% for panels, the large number of VUS reported by commercial laboratories has significant resource implications. Our results support the need for greater adherence to the recommendations on the prenatal reporting of VUS and the importance of a multidisciplinary approach that brings together clinical and laboratory expertise in prenatal genetics and genomics.
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- 2022
3. The Clinical Variant Analysis Tool: Analyzing the evidence supporting reported genomic variation in clinical practice
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Hui-Lin Chin, Nour Gazzaz, Stephanie Huynh, Iulia Handra, Lynn Warnock, Ashley Moller-Hansen, Pierre Boerkoel, Julius O.B. Jacobsen, Christèle du Souich, Nan Zhang, Kent Shefchek, Leah M. Prentice, Nicole Washington, Melissa Haendel, Linlea Armstrong, Lorne Clarke, Wenhui Laura Li, Damian Smedley, Peter N. Robinson, and Cornelius F. Boerkoel
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Exome Sequencing ,Genetic Variation ,Humans ,Exome ,Genetic Testing ,Genomics ,Article ,Genetics (clinical) - Abstract
PURPOSE: Genomic test results, regardless of laboratory variant classification, require clinical practitioners to judge the applicability of a variant for medical decisions. Teaching and standardizing clinical interpretation of genomic variation calls for a methodology or tool. METHODS: To generate such a tool, we distilled the Clinical Genome Resource framework of causality and the American College of Medical Genetics/Association of Molecular Pathology and Quest Diagnostic Laboratory scoring of variant deleteriousness into the Clinical Variant Analysis Tool (CVAT). Applying this to 289 clinical exome reports, we compared the performance of junior practitioners with that of experienced medical geneticists and assessed the utility of reported variants. RESULTS: CVAT enabled performance comparable to that of experienced medical geneticists. In total, 124 of 289 (42.9%) exome reports and 146 of 382 (38.2%) reported variants supported a diagnosis. Overall, 10.5% (1 pathogenic [P] or likely pathogenic [LP] variant and 39 variants of uncertain significance [VUS]) of variants were reported in genes without established disease association; 20.2% (23 P/LP and 54 VUS) were in genes without sufficient phenotypic concordance; 7.3% (15 P/LP and 13 VUS) conflicted with the known molecular disease mechanism; and 24% (91 VUS) had insufficient evidence for deleteriousness. CONCLUSION: Implementation of CVAT standardized clinical interpretation of genomic variation and emphasized the need for collaborative and transparent reporting of genomic variation.
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- 2022
4. The practice of genomic medicine: A delineation of the process and its governing principles
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Julia Handra, Adrienne Elbert, Nour Gazzaz, Ashley Moller-Hansen, Stephanie Hyunh, Hyun Kyung Lee, Pierre Boerkoel, Emily Alderman, Erin Anderson, Lorne Clarke, Sara Hamilton, Ronnalea Hamman, Shevaun Hughes, Simon Ip, Sylvie Langlois, Mary Lee, Laura Li, Frannie Mackenzie, Millan S. Patel, Leah M. Prentice, Karan Sangha, Laura Sato, Kimberly Seath, Margaret Seppelt, Anne Swenerton, Lynn Warnock, Jessica L. Zambonin, Cornelius F. Boerkoel, Hui-Lin Chin, and Linlea Armstrong
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General Medicine - Abstract
Genomic medicine, an emerging medical discipline, applies the principles of evolution, developmental biology, functional genomics, and structural genomics within clinical care. Enabling widespread adoption and integration of genomic medicine into clinical practice is key to achieving precision medicine. We delineate a biological framework defining diagnostic utility of genomic testing and map the process of genomic medicine to inform integration into clinical practice. This process leverages collaboration and collective cognition of patients, principal care providers, clinical genomic specialists, laboratory geneticists, and payers. We detail considerations for referral, triage, patient intake, phenotyping, testing eligibility, variant analysis and interpretation, counseling, and management within the utilitarian limitations of health care systems. To reduce barriers for clinician engagement in genomic medicine, we provide several decision-making frameworks and tools and describe the implementation of the proposed workflow in a prototyped electronic platform that facilitates genomic care. Finally, we discuss a vision for the future of genomic medicine and comment on areas for continued efforts.
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- 2023
5. Ulcerated amelanotic melanoma of the ear in an 11 year old with Fitzpatrick VI skin type: A case report
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Jefferson Terry, Wingfield Rehmus, Linlea Armstrong, Douglas J. Courtemanche, Matthew N. Roberts, J. Paul Moxham, Melissa Harvey, and Allison Gregory
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Fitzpatrick Skin Type VI ,medicine.medical_specialty ,Skin type ,business.industry ,Melanoma ,Dermatology ,medicine.disease ,Nodular melanoma ,medicine.anatomical_structure ,Pediatrics, Perinatology and Child Health ,medicine ,Therapy systemic ,Nivolumab ,business ,Amelanotic melanoma ,neoplasms ,Lymph node - Abstract
Melanoma is rare in pediatric patients and even more so in those with darker Fitzpatrick skin types. Although risk factors for conventional melanoma are similar in both adult and pediatric cases, the presentation of melanoma in pediatric patients is often distinct from adults. Here, we describe a case of amelanotic ulcerated nodular melanoma with regional lymph node metastases treated with nivolumab in a patient with Fitzpatrick skin type VI.
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- 2021
6. Bi-allelic variants in the ER quality-control mannosidase gene EDEM3 cause a congenital disorder of glycosylation
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Ana Berta Sousa, Anneke J.A. Kievit, Marjon van Slegtenhorst, Nicholas J. Hand, Kosuke Izumi, Paula Jorge, Andrew C. Edmondson, Elisa De Franco, Linlea Armstrong, Michael E. March, Dirk Lefeber, Hans van Bokhoven, Miao He, Sian Ellard, Marina P Hommersom, Serwet Demirdas, Elaine H. Zackai, Fleur S van Dijk, Anna Lehman, Avni Santani, Daniel L. Polla, Daniel J. Rader, Arjan P.M. de Brouwer, Sandrine Duvet, Xin Bi, Sophie C. Huffels, Dmitriy Niyazov, Céline Schulz, Clinical Genetics, and Repositório da Universidade de Lisboa
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Male ,Glycosylation ,Mouse ,Developmental Disabilities ,Endoplasmic Reticulum ,Compound heterozygosity ,chemistry.chemical_compound ,Congenital Disorders of Glycosylation ,0302 clinical medicine ,EIF2AK3 ,Child ,Genetics (clinical) ,Exome sequencing ,0303 health sciences ,Tunicamycin ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,Pedigree ,Mannosidase ,Child, Preschool ,N-glycan ,Female ,Adolescent ,Biology ,Cell Line ,03 medical and health sciences ,Polysaccharides ,alpha-Mannosidase ,Intellectual Disability ,Report ,Genetics ,medicine ,Humans ,Proteostasis Deficiencies ,Gene ,Alleles ,Glycoproteins ,030304 developmental biology ,Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] ,Endoplasmic reticulum ,Calcium-Binding Proteins ,Infant ,medicine.disease ,Molecular biology ,carbohydrates (lipids) ,Dysmorphism ,chemistry ,Mutation ,Unfolded protein response ,High-mannose ,CDG ,EDEM3 ,Congenital disorder of glycosylation ,030217 neurology & neurosurgery - Abstract
© 2021 American Society of Human Genetics, EDEM3 encodes a protein that converts Man8GlcNAc2 isomer B to Man7-5GlcNAc2. It is involved in the endoplasmic reticulum-associated degradation pathway, responsible for the recognition of misfolded proteins that will be targeted and translocated to the cytosol and degraded by the proteasome. In this study, through a combination of exome sequencing and gene matching, we have identified seven independent families with 11 individuals with bi-allelic protein-truncating variants and one individual with a compound heterozygous missense variant in EDEM3. The affected individuals present with an inherited congenital disorder of glycosylation (CDG) consisting of neurodevelopmental delay and variable facial dysmorphisms. Experiments in human fibroblast cell lines, human plasma, and mouse plasma and brain tissue demonstrated decreased trimming of Man8GlcNAc2 isomer B to Man7GlcNAc2, consistent with loss of EDEM3 enzymatic activity. In human cells, Man5GlcNAc2 to Man4GlcNAc2 conversion is also diminished with an increase of Glc1Man5GlcNAc2. Furthermore, analysis of the unfolded protein response showed a reduced increase in EIF2AK3 (PERK) expression upon stimulation with tunicamycin as compared to controls, suggesting an impaired unfolded protein response. The aberrant plasma N-glycan profile provides a quick, clinically available test for validating variants of uncertain significance that may be identified by molecular genetic testing. We propose to call this deficiency EDEM3-CDG., This work was supported by the EU FP7 large-scale integrating project Genetic and Epigenetic Networks in Cognitive Dysfunction (241995) (to H.v.B.); National Institutes of Health (NIH) grants 5R01GM115730-03 (to M.H.), U54 NS115198 (to A.C.E. and M.H.), and T32GM008638 (to A.C.E.); and the Transatlantic Network of Excellence grant (10CVD03) from the Fondation Leducq and NIH NHGRI U01HG006398 (to D.J.R.). Family 4 was enrolled in the CAUSES Study; investigators include Shelin Adam, Christele Du Souich, Alison Elliott, Anna Lehman, Jill Mwenifumbo, Tanya Nelson, Clara Van Karnebeek, and Jan Friedman; it is funded by Mining for Miracles, British Columbia Children’s Hospital Foundation (grant number F15-01355) and Genome British Columbia (grant number F16-02276). D.L.P. is recipient of a CAPES Fellowship (99999.013311/2013-01). X.B. is supported by an AHA career development award (19CDA34630032).
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- 2021
7. Primary cutaneous follicle center lymphoma of the medial canthus of the eye in an 11-year old
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Paul R. D'Alessandro, Andrea C. Lo, Martin H. Spencer, Pedro Farinha, Linlea Armstrong, Peter J. Dolman, and Sylvia Cheng
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Skin Neoplasms ,Oncology ,Pediatrics, Perinatology and Child Health ,Lacrimal Apparatus ,Humans ,Hematology ,Child ,Lymphoma, Follicular - Published
- 2022
8. Comment on: Primary Cutaneous Lymphomas in Children and Adolescents Primary cutaneous follicle center lymphoma of the medial canthus of the eye in an eleven year old
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Paul D'Alessandro, Andrea Lo, Martin Spencer, Pedro Farinha, Linlea Armstrong, Peter Dolman, and Sylvia Cheng
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- 2022
9. Clinical spectrum of individuals with pathogenic N F1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype–phenotype study in neurofibromatosis type 1
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Giulio Piluso, Katharina Wimmer, Veronica Saletti, Eniko K. Pivnick, Geraldine Kelly-Mancuso, Karen W. Gripp, Cristin Griffis, Louanne Hudgins, Alessandro De Luca, Michael F. Wangler, M. Daniela D'Agostino, Marica Eoli, Cynthia M. Powell, Laura A. Baker, Mayra Martinez Ojeda, Silvia Esposito, Elizabeth A. Sellars, Kory Keller, David D. Weaver, James T. Bennett, Nicole J. Ullrich, Allison L. Goetsch, Donald Basel, Bruce R. Korf, Stephanie Fox, Katelyn Hodge, Laura Dosa, Robert S. Greenwood, Mario Bengala, Andrea M. Lewis, Ruth Sheffer, Valentina Pinna, Fanny Cortés, Dusica Babovic-Vuksanovic, Aaina Kochhar, Rosemarie Smith, Concepción Hernández-Chico, Elizabeth Siqveland, Robert Listernick, Lola K. Clarkson, Punita Gupta, E. Haan, Martin B. Delatycki, Amy Theos, Noa Ruhrman Shahar, Teresa Giugliano, Carey McDougall, Mitch Cunningham, David W. Stockton, Tom Callens, Maria Cristina Digilio, Yunjia Chen, Ludwine Messiaen, Eva Trevisson, Samantha A. Schrier Vergano, Caleb Rogers, Magdalena Koczkowska, Kathleen Claes, Christine Fauth, Jan Liebelt, Pamela Trapane, Eric Johns, John M. Slopis, Chelsea Chambers, Tamara L. Haygarth, Lesley K. McGregor, Alberto Spalice, Małgorzata J.M. Nowaczyk, Mary Ella M Pierpont, Kaleb Yohay, Alicia Gomes, Vickie Zurcher, Gail E. Tomlinson, Angie W. Lichty, Stephanie E Wallace, Rachel K. Hachen, Isabelle Maystadt, S. Lane Rutledge, Yael Goldberg, Grace Tran, Ulrich A. Schatz, Allison Schreiber, Jenneke van den Ende, Michael J. Lyons, Mary Louise Freckmann, Kim Armfield Uhas, Alesha D. Hicks, Maurizio Clementi, Haley Streff, June Ortenberg, John Pappas, Nancy J. Mendelsohn, Sandra Janssens, Karin Panzer, Yolanda Martin, Elaine H. Zackai, Sandra Giustini, Linlea Armstrong, Katherine A. Bosanko, Angela Sharp, Daryl A. Scott, Jonathan Zonana, Robert J. Hopkin, Eric Legius, Dinel A. Pond, Daniela Melis, Claudia Santoro, and Sarah A. Sandaradura
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congenital, hereditary, and neonatal diseases and abnormalities ,0303 health sciences ,medicine.medical_specialty ,education.field_of_study ,Pulmonic stenosis ,030305 genetics & heredity ,Population ,Spinal neurofibromas ,Biology ,medicine.disease ,Phenotype ,Gastroenterology ,nervous system diseases ,03 medical and health sciences ,Internal medicine ,Cohort ,Genetics ,medicine ,Missense mutation ,Noonan syndrome ,Neurofibromatosis ,education ,Genetics (clinical) ,030304 developmental biology - Abstract
We report 281 individuals carrying a pathogenic recurrent NF1 missense variant at p.Met1149, p.Arg1276, or p.Lys1423, representing three nontruncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% confidence interval: 20.5-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276, or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared with the "classic" NF1-affected cohorts (all p < .0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all p < .0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (p < .0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population.
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- 2019
10. Performance of the McGill Interactive Pediatric OncoGenetic Guidelines for Identifying Cancer Predisposition Syndromes
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Josée Brossard, Kathleen Felton, Jemma Say, Adam Fleming, Valerie Larouche, Ronald Grant, Katherine A Blood, Uri Tabori, Melissa Tachdjian, Chantel Cacciotti, Rawan Hammad, Noelle Cullinan, Catherine Goudie, Vijay Ramaswamy, Lucie Lafay-Cousin, Kalene van Engelen, Kim E. Nichols, Ledia Brunga, Linlea Armstrong, Kimberly Caswell, Stephanie Vairy, Jonathan D. Wasserman, Mary Egan Clark, Conrad V. Fernandez, Katherine M. Tucker, Nandini Dendukuri, James A. Whitlock, Ian Schiller, David Malkin, Gino Somers, Annie-Kim Toupin, Nada Jabado, M. Stephen Meyn, Nicolas Waespe, Sonia Cellot, Daniel Sinnett, Paul Gibson, My Linh Thibodeau, Donna L. Johnston, William D. Foulkes, Rebecca J. Deyell, Angela Punnett, David S. Ziegler, Irene Lara-Corrales, Junne Kamihara, Sarah R. Kane, Meghan Pike, Natalie Mathews, Catherine Clinton, Renee Perrier, Lynn W. Harrison, Meredith S. Irwin, Noemi Fuentes-Bolanos, Orli Michaeli, Meera Warby, Adam Shlien, Leora Witkowski, Anita Villani, Hallie Coltin, Paul C. Nathan, and Lara Reichman
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Cancer Research ,medicine.medical_specialty ,Referral ,Genetic counseling ,Internal medicine ,Neoplasms ,Medicine ,Humans ,In patient ,Genetic Predisposition to Disease ,Genetic Testing ,Medical diagnosis ,610 Medicine & health ,Child ,Early Detection of Cancer ,Genetic testing ,Original Investigation ,medicine.diagnostic_test ,business.industry ,Cancer predisposition ,Cancer ,Syndrome ,medicine.disease ,Oncology ,Child, Preschool ,business ,Risk assessment ,360 Social problems & social services - Abstract
Importance Prompt recognition of a child with a cancer predisposition syndrome (CPS) has implications for cancer management, surveillance, genetic counseling, and cascade testing of relatives. Diagnosis of CPS requires practitioner expertise, access to genetic testing, and test result interpretation. This diagnostic process is not accessible in all institutions worldwide, leading to missed CPS diagnoses. Advances in electronic health technology can facilitate CPS risk assessment. Objective To evaluate the diagnostic accuracy of a CPS prediction tool (McGill Interactive Pediatric OncoGenetic Guidelines [MIPOGG]) in identifying children with cancer who have a low or high likelihood of having a CPS. Design, Setting, and Participants In this international, multicenter diagnostic accuracy study, 1071 pediatric (
- Published
- 2021
11. Genome-wide sequencing and the clinical diagnosis of genetic disease: The CAUSES study
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Alison M. Elliott, Shelin Adam, Christèle du Souich, Anna Lehman, Tanya N. Nelson, Clara van Karnebeek, Emily Alderman, Linlea Armstrong, Gudrun Aubertin, Katherine Blood, Cyrus Boelman, Cornelius Boerkoel, Karla Bretherick, Lindsay Brown, Chieko Chijiwa, Lorne Clarke, Madeline Couse, Susan Creighton, Abby Watts-Dickens, William T. Gibson, Harinder Gill, Maja Tarailo-Graovac, Sara Hamilton, Harindar Heran, Gabriella Horvath, Lijia Huang, Gurdip K. Hulait, David Koehn, Hyun Kyung Lee, Suzanne Lewis, Elena Lopez, Kristal Louie, Karen Niederhoffer, Allison Matthews, Kirsten Meagher, Junran J. Peng, Millan S. Patel, Simone Race, Phillip Richmond, Rosemarie Rupps, Ramona Salvarinova, Kimberly Seath, Kathryn Selby, Michelle Steinraths, Sylvia Stockler, Kaoru Tang, Christine Tyson, Margot van Allen, Wyeth Wasserman, Jill Mwenifumbo, Jan M. Friedman, Paediatric Metabolic Diseases, ANS - Cellular & Molecular Mechanisms, Paediatrics, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
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genome sequencing ,genetic counseling ,diagnostic rate ,multidisciplinary approach ,reanalysis ,Molecular Medicine ,exome sequencing ,reinterpretation ,Genetics (clinical) - Abstract
Genome-wide sequencing (GWS) is a standard of care for diagnosis of suspected genetic disorders, but the proportion of patients found to have pathogenic or likely pathogenic variants ranges from less than 30% to more than 60% in reported studies. It has been suggested that the diagnostic rate can be improved by interpreting genomic variants in the context of each affected individual's full clinical picture and by regular follow-up and reinterpretation of GWS laboratory results. Trio exome sequencing was performed in 415 families and trio genome sequencing in 85 families in the CAUSES study. The variants observed were interpreted by a multidisciplinary team including laboratory geneticists, bioinformaticians, clinical geneticists, genetic counselors, pediatric subspecialists, and the referring physician, and independently by a clinical laboratory using standard American College of Medical Genetics and Genomics (ACMG) criteria. Individuals were followed for an average of 5.1 years after testing, with clinical reassessment and reinterpretation of the GWS results as necessary. The multidisciplinary team established a diagnosis of genetic disease in 43.0% of the families at the time of initial GWS interpretation, and longitudinal follow-up and reinterpretation of GWS results produced new diagnoses in 17.2% of families whose initial GWS interpretation was uninformative or uncertain. Reinterpretation also resulted in rescinding a diagnosis in four families (1.9%). Of the families studied, 33.6% had ACMG pathogenic or likely pathogenic variants related to the clinical indication. Close collaboration among clinical geneticists, genetic counselors, laboratory geneticists, bioinformaticians, and individuals’ primary physicians, with ongoing follow-up, reanalysis, and reinterpretation over time, can improve the clinical value of GWS.
- Published
- 2021
12. Loss of BRG1 (SMARCA4) Immunoexpression in a Pediatric Non-Central Nervous System Tumor Cohort
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Jonathan W. Bush, Jessica Saunders, Katrina M Ingley, Xiu Qing Wang, Linlea Armstrong, Tony Ng, Melissa Harvey, and Christopher Dunham
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Tissue microarray ,business.industry ,General Medicine ,medicine.disease ,Small-cell carcinoma ,Phenotype ,Pathology and Forensic Medicine ,Rhabdoid Tumor Predisposition Syndrome ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Germline mutation ,030220 oncology & carcinogenesis ,Pediatrics, Perinatology and Child Health ,SMARCA4 ,Medicine ,Immunohistochemistry ,business ,Immunostaining - Abstract
Malignant rhabdoid tumors and atypical teratoid/rhabdoid tumors of the central nervous system are primitive malignancies associated with a poor prognosis. These tumors have previously been characterized by inactivation of the switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex protein integrase interactor 1 (INI1), encoded by the SMARCB1 gene. In the last decade, sporadic publications have shown that a different SWI/SNF protein, brahma-related gene 1 (BRG1), encoded by the SMARCA4 gene, is associated with a similar rhabdoid phenotype and possible germline mutation termed rhabdoid tumor predisposition syndrome type 2. We sought to determine the presence of BRG1 expression in pediatric embryonal tumors. Using a local tissue microarray consisting of 28 tumors diagnosed as having an undifferentiated, polyphenotypic, or rhabdoid morphology, expression of BRG1 by immunohistochemistry was performed. Four cases showed loss of INI1, while 3 of the remaining 24 cases demonstrated loss of BRG1. Two cases were diagnosed as soft tissue sarcomas, and 1 case was diagnosed as a small cell carcinoma of the ovary, hypercalcemic type. Survival ranged from less than 6 months after diagnosis to more than 5 years at the time of last follow-up. In conclusion, we demonstrate that BRG1 immunohistochemistry is a useful second-line immunostain for the workup of undifferentiated, polyphenotypic or rhabdoid pediatric tumors that demonstrate retained expression of INI1.
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- 2019
13. RAPIDOMICS: rapid genome-wide sequencing in a neonatal intensive care unit—successes and challenges
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Suzanne M E Lewis, Leah Tooman, Horacio Osiovich, Margot I. Van Allen, Linlea Armstrong, Harinder Gill, Jan M. Friedman, Jan Christilaw, Millan S. Patel, Ilaria Guella, Lorne A. Clarke, Matthew J. Farrer, Tara Candido, Anna Lehman, Anne Synnes, Alfonso Solimano, Daniel M. Evans, Joseph Ting, Margaret L. McKinnon, Christèle du Souich, William T. Gibson, Sarah M. Nikkel, Alison M. Elliott, and Pascal M. Lavoie
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Male ,Pediatrics ,medicine.medical_specialty ,Neonatal intensive care unit ,Critical Illness ,Genetic counseling ,Clinical Decision-Making ,Genetic Counseling ,Pilot Projects ,Genome ,03 medical and health sciences ,Health services ,0302 clinical medicine ,Intensive Care Units, Neonatal ,030225 pediatrics ,Intensive care ,Outcome Assessment, Health Care ,Exome Sequencing ,Humans ,Medicine ,Genetic Testing ,030212 general & internal medicine ,Exome sequencing ,business.industry ,Patient Selection ,Genetic Diseases, Inborn ,Infant, Newborn ,Microarray Analysis ,Infant mortality ,Preliminary diagnosis ,Pediatrics, Perinatology and Child Health ,Intensive Care, Neonatal ,Female ,business - Abstract
Genetic disorders are one of the leading causes of infant mortality and are frequent in neonatal intensive care units (NICUs). Rapid genome-wide sequencing (GWS; whole genome or exome sequencing (ES)), due to its diagnostic capabilities and immediate impacts on medical management, is becoming an appealing testing option in the NICU setting. RAPIDOMICS was a trio-based rapid ES pilot study of 25 babies with suspected genetic disorders in the BC Women's Hospital NICU. ES and bioinformatic analysis were performed after careful patient ascertainment. Trio analysis was performed using an in-house pipeline reporting variants in known disease-causing genes. Variants interpreted by the research team as definitely or possibly causal of the infant's phenotype were Sanger validated in a clinical laboratory. The average time to preliminary diagnosis was 7.2 days. Sanger validation was pursued in 15 patients for 13 autosomal dominant and 2 autosomal recessive disorders, with an overall diagnostic rate (partial or complete) of 60%.Conclusion: In total, 72% of patients enrolled had a genomic diagnosis achieved through ES, multi-gene panel testing or chromosomal microarray analysis. Among these, there was an 83% rate of significant and immediate impact on medical decision-making directly related to new knowledge of the diagnosis. Health service implementation challenges and successes are discussed. What is Known: • Rapid genome-wide sequencing in the neonatal intensive care setting has a greater diagnostic hit rate and impact on medical management than conventional genetic testing. However, the impact of consultation with genetics and patient ascertainment requires further investigation. What is New: • This study demonstrates the importance of genetic consultation and careful patient selection prior to pursuing exome sequencing (ES). • In total, 15/25 (60%) patients achieved a diagnosis through ES and 18/25 (72%) through ES, multi-gene panel testing or chromosomal microarray analysis with 83% of those having immediate effects on medical management.
- Published
- 2019
14. Perioperative Hypotensive Crisis in an Adolescent with a Pancreatic VIPoma and MEN1-Gene Variant
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Eric M. Webber, Constadina Panagiotopoulos, Alejandra Acosta-Gualandri, Kung-Ting Kao, Linlea Armstrong, and Tiffany Wong
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medicine.medical_specialty ,Hypercalcaemia ,business.industry ,Endocrinology, Diabetes and Metabolism ,Vasoactive intestinal peptide ,Octreotide ,Context (language use) ,Perioperative ,medicine.disease ,Gastroenterology ,Endocrinology ,Internal medicine ,Pediatrics, Perinatology and Child Health ,medicine ,Pancreatic Vipoma ,business ,Multiple endocrine neoplasia ,VIPoma ,medicine.drug - Abstract
Background: Vasoactive intestinal peptide-secreting tumours (VIPomas) lead to high-volume secretory diarrhoea with hypokalaemia, as well as hyperglycaemia and hypercalcaemia. Diagnosis is often delayed. Case Description: We present a 13-year-old girl with a distal pancreatic VIPoma diagnosed on her second hospital presentation who became severely hypotensive on anaesthetic induction prior to tumour removal, likely due to the vasodilatory effect of supraphysiological VIP levels. Prior to the second surgical attempt, an octreotide infusion was started preoperatively to suppress systemic VIP levels and counter the potential for VIP-induced hypotension upon tumour manipulation, and the tumour was successfully resected. Hyperparathyroidism and history of GI tumour resection were subsequently identified in the father, and the two members were found to have a heterozygous variant of uncertain significance in the multiple endocrine neoplasia type 1 (MEN1) gene. However, as this family meets the diagnostic criteria for MEN1 clinically, ongoing surveillance for MEN1 tumours and genetic counseling for at-risk family members are required despite the non-pathogenic genetic result. Conclusion: This case highlights the importance of screening for a VIPoma in patients with high-volume secretory diarrhoea and preventing cardiovascular complications with perioperative VIP suppression. Furthermore, careful interpretation of genetic results within the clinical context is required.
- Published
- 2018
15. Crizotinib response in a neuroblastoma patient with a constitutional mosaic anaplastic lymphoma kinase I1170N‐activating mutation
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Kim Seath, Sharon Gershony, Linlea Armstrong, Sean D. Young, Meredith S. Irwin, Melissa Harvey, and Rebecca J. Deyell
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Lung Neoplasms ,Crizotinib ,business.industry ,Hematology ,medicine.disease ,Activating mutation ,Neuroblastoma ,Oncology ,Mutation ,Pediatrics, Perinatology and Child Health ,Cancer research ,Humans ,Medicine ,Anaplastic lymphoma kinase ,Anaplastic Lymphoma Kinase ,business ,Protein Kinase Inhibitors ,medicine.drug - Published
- 2021
16. Somatic mosaicism detected by genome-wide sequencing in 500 parent–child trios with suspected genetic disease: clinical and genetic counseling implications
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Elena Lopez, Courtney B Cook, Michelle Demos, Alison M. Elliott, Millan S. Patel, Linlea Armstrong, Kathryn Selby, Harinder Gill, Lorne A. Clarke, Cornelius F. Boerkoel, Causes Study, Jan M. Friedman, Ziad Abu-Sharar, Christèle du Souich, and William T. Gibson
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Genetics ,Proband ,Sanger sequencing ,Mosaicism ,Genetic counseling ,General Medicine ,Disease ,Biology ,Genome ,DNA sequencing ,symbols.namesake ,intellectual disability, moderate ,Mutation (genetic algorithm) ,symbols ,intellectual disability, mild ,intellectual disability, profound ,Humans ,Exome ,Research Article - Abstract
Identifying genetic mosaicism is important in establishing a diagnosis, assessing recurrence risk, and providing accurate genetic counseling. Next-generation sequencing has allowed for the identification of mosaicism at levels below those detectable by conventional Sanger sequencing or chromosomal microarray analysis. The CAUSES Clinic was a pediatric translational trio-based genome-wide (exome or genome) sequencing study of 500 families (531 children) with suspected genetic disease at BC Children's and Women's Hospitals. Here we present 12 cases of apparent mosaicism identified in the CAUSES cohort: nine cases of parental mosaicism for a disease-causing variant found in a child and three cases of mosaicism in the proband for a de novo variant. In six of these cases, there was no evidence of mosaicism on Sanger sequencing—the variant was not detected on Sanger sequencing in three cases, and it appeared to be heterozygous in three others. These cases are examples of six clinical manifestations of mosaicism: a proband with classical clinical features of mosaicism (e.g., segmental abnormalities of skin pigmentation or asymmetrical growth of bilateral body parts), a proband with unusually mild manifestations of a disease, a mosaic proband who is clinically indistinguishable from the constitutive phenotype, a mosaic parent with no clinical features of the disease, a mosaic parent with mild manifestations of the disease, and a family in which both parents are unaffected and two siblings have the same disease-causing constitutional mutation. Our data demonstrate the importance of considering the possibility of mosaicism whenever exome or genome sequencing is performed and that its detection via genome-wide sequencing can permit more accurate genetic counseling.
- Published
- 2021
17. Coaching the coaches: Employing role modeling and coaching as a faculty development strategy
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Ingrid V. Price, Heather L. Buckley, Linlea Armstrong, and Maria Hubinette
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Employment ,Medical education ,020205 medical informatics ,business.industry ,Role modeling ,education ,Professional development ,Medical school ,Mentoring ,02 engineering and technology ,General Medicine ,Faculty ,Coaching ,Education ,03 medical and health sciences ,0302 clinical medicine ,Surveys and Questionnaires ,0202 electrical engineering, electronic engineering, information engineering ,Humans ,030212 general & internal medicine ,Faculty development ,Reflection (computer graphics) ,business ,Psychology ,Goal setting - Abstract
Faculty members at a Canadian medical school coach small groups of students to support their professional development through goal setting and guided reflection about clinical experiences. These gr...
- Published
- 2021
18. Establishing a Framework for the Clinical Translation of Germline Findings in Precision Oncology
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Steven J.M. Jones, Dean A. Regier, Yaoqing Shen, Rebecca J. Deyell, Ana Fisic, Janessa Laskin, Sean D. Young, Alexandra Fok, Dan Renouf, S. Rod Rassekh, Stephen Yip, Alice Virani, Eric Y. Zhao, Aly Karsan, Karen A. Gelmon, Emma Titmuss, Shirin Abadi, Erin Pleasance, Ian Bosdet, Martin L. Jones, My Linh Thibodeau, Linlea Armstrong, Stephen Chia, Sophie Sun, Geraldine Aubert, Katherine Dixon, Marco A. Marra, Howard John Lim, and Kasmintan A. Schrader
- Subjects
0303 health sciences ,Cancer Research ,business.industry ,MEDLINE ,Cancer ,Genomics ,Oncogenomics ,Bioinformatics ,medicine.disease ,Germline ,03 medical and health sciences ,0302 clinical medicine ,Oncology ,Precision oncology ,030220 oncology & carcinogenesis ,Cancer screening ,Commentary ,Medicine ,Clinical significance ,AcademicSubjects/MED00010 ,business ,030304 developmental biology - Abstract
Inherited genetic variation has important implications for cancer screening, early diagnosis, and disease prognosis. A role for germline variation has also been described in shaping the molecular landscape, immune response, microenvironment, and treatment response of individual tumors. However, there is a lack of consensus on the handling and analysis of germline information that extends beyond known or suspected cancer susceptibility in large-scale cancer genomics initiatives. As part of the Personalized OncoGenomics program in British Columbia, we performed whole-genome and transcriptome sequencing in paired tumor and normal tissues from advanced cancer patients to characterize the molecular tumor landscape and identify putative targets for therapy. Overall, our experience supports a multidisciplinary and integrative approach to germline data management. This includes a need for broader definitions and standardized recommendations regarding primary and secondary germline findings in precision oncology. Here, we propose a framework for identifying, evaluating, and returning germline variants of potential clinical significance that may have indications for health management beyond cancer risk reduction or prevention in patients and their families.
- Published
- 2020
19. Case Series: A Kindred With Eruptive Vellus Hair Cysts and Systemic Features
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Magdalena Martinka, Margot I. Van Allen, Marisa G Ponzo, Jan P. Dutz, and Linlea Armstrong
- Subjects
Heart Defects, Congenital ,Joint Instability ,Male ,Joint hypermobility ,Pathology ,medicine.medical_specialty ,Dermatology ,Craniofacial Abnormalities ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,Humans ,Medicine ,Steatocystoma multiplex ,Cysts ,business.industry ,Genodermatosis ,medicine.disease ,Trunk ,Pedigree ,Child, Preschool ,030220 oncology & carcinogenesis ,Vellus hair ,Cardiac defects ,Female ,Surgery ,Lipoma ,Hair Diseases ,business ,Facial Dermatoses - Abstract
Eruptive vellus hair cysts (EVHCs) often occur on the trunk and limbs. Facial involvement is uncommon. Autosomal dominant inheritance has been described, but associated extracutaneous anomalies have not. We describe a 4-patient kindred presenting with multiple facial EVHCs and an association of preauricular pits, lipomas, joint hypermobility, and cardiac defects. Histopathologic examination confirmed the diagnosis of EVHCs in 3 affected individuals. We propose that facial EVHCs may indicate the presence of an inherited autosomal dominant disorder with extracutaneous manifestations. Extracutaneous manifestations noted in the kindred have been sporadically described in association with steatocystoma multiplex (SM), a condition occasionally noted in the presence of EVHCs, further supporting an association between these disorders.
- Published
- 2017
20. Loss of BRG1 (
- Author
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Jessica, Saunders, Katrina, Ingley, Xiu Qing, Wang, Melissa, Harvey, Linlea, Armstrong, Tony, Ng, Christopher, Dunham, and Jonathan, Bush
- Subjects
Male ,Adolescent ,DNA Helicases ,Infant, Newborn ,Infant ,Nuclear Proteins ,SMARCB1 Protein ,Immunohistochemistry ,Pediatrics ,Cohort Studies ,Phenotype ,Child, Preschool ,Humans ,Female ,Child ,Rhabdoid Tumor ,Transcription Factors - Abstract
Malignant rhabdoid tumors and atypical teratoid/rhabdoid tumors of the central nervous system are primitive malignancies associated with a poor prognosis. These tumors have previously been characterized by inactivation of the switch/sucrose nonfermenting (SWI/SNF) chromatin remodeling complex protein integrase interactor 1 (INI1), encoded by the
- Published
- 2019
21. Bye to burnout: intergenerational narratives break barriers
- Author
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Melissa Bota, Brett Schrewe, Meghan Matos, Linlea Armstrong, and Jaeyun Yoo
- Subjects
Medical psychology ,Faculty, Medical ,Narration ,Students, Medical ,Writing ,MEDLINE ,Internship and Residency ,General Medicine ,Burnout ,Education ,Intergenerational Relations ,Humans ,Medicine ,Narrative ,Sociology ,Social psychology ,Burnout, Professional - Published
- 2019
22. The Orthopaedic Management of Human Disorganization Syndrome
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Judy So, Kishore Mulpuri, Cindy Verchere, Kevin Smit, Emily K. Schaeffer, and Linlea Armstrong
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Flexion contracture ,medicine.medical_specialty ,business.industry ,Knee flexion contracture ,Case Report ,musculoskeletal system ,medicine.disease ,Pterygium ,Surgery ,Guided growth ,Rare case ,Flexion deformity ,medicine ,Orthopedics and Sports Medicine ,Surgical excision ,business ,Tethered Cord - Abstract
Introduction: Human disorganization syndrome (HDS) is an extremely rare congenital syndrome characterized by a seemingly random distribution of multiple developmental anomalies involving all three germinal layers. Case Report: We report a rare case of a female child whose congenital anomalies are consistent with HDS. The orthopaedic features of this patient include a popliteus pterygium with an associated flexion contracture secondary to an elongated biceps femoris tendon that attached to the gastrocnemius-soleus muscle complex, two finger-like appendages, a tethered cord, a lipomeningomyelocele at the level of L5, and a leglength discrepancy. The patient was treated with a splinting program, release of the biceps femoris tendon at its erroneous insertion from the gastrocs-soleus, and surgical excision of the finger-like appendages. She underwent three subsequent soft-tissue releases to address recurrence of the knee flexion contracture and an anteromedial and lateral distal femoral eight plate procedure for guided growth and slow correction of the remaining flexion deformity. Conclusion: The treatment of HDS can be quite complex and can present with a variety of anomalies with distinctive orthopaedic features correctable with surgical management, including soft-tissue releases, excision of appendages, and growth modulation.
- Published
- 2020
23. PTPRD copy number variants and Ewing's sarcoma: Strengthening the association and therapeutic implications
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Jeffrey H. Davis, Fahed Halal, Kimberly I. Seath, Avi Saskin, Frédérique Tihy, Emmanuelle Lemyre, and Linlea Armstrong
- Subjects
Male ,Cancer Research ,Tumor suppressor gene ,Adolescent ,DNA Copy Number Variations ,Somatic cell ,Receptor-Like Protein Tyrosine Phosphatases, Class 2 ,Ewing's sarcoma ,Bone Neoplasms ,Sarcoma, Ewing ,Biology ,medicine.disease ,Germline ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Genetics ,Cancer research ,medicine ,PMS2 ,Neoplasm ,Humans ,Sarcoma ,Copy-number variation ,Molecular Biology - Abstract
Ewing sarcoma (ES), a common pediatric primary bone neoplasm, has a well-defined genomic landscape with various predisposing genomic elements including TP53, PMS2 and RET. Additionally, germline and somatic variants in protein tyrosine phosphatase delta (PTPRD), a tumor suppressor gene, have been identified in a limited number of ES patients. Here we present an ES patient, remarkable in terms of his young age and extent at presentation, found to have a PTPRD CNV. We explore the pathogenicity of this CNV, describe the patient's clinical course and touch upon the potential therapeutic implications in this subset of patients.
- Published
- 2018
24. Mutations in MAST1 Cause Mega-Corpus-Callosum Syndrome with Cerebellar Hypoplasia and Cortical Malformations
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William B. Dobyns, Maria Fernanda Martinez-Reza, Jamel Chelly, Tessa van Dijk, Lydie Burglen, Martin W. Breuss, Gregory M. Cooper, Stefano Lise, Nadia Bahi-Buisson, Norine Voisin, Usha Kini, Linlea Armstrong, Nicholas J. Cowan, Stéphanie Valence, Andrea Wenninger-Weinzierl, Thomas A. Leonard, Frank Baas, Lukas Landler, Ennio Del Giudice, Jonathan A. Bernstein, Ghayda Mirzaa, Guoling Tian, Kimberly A. Aldinger, Bregje W.M. van Bon, Alexandre Reymond, Tyler Mark Pierson, Giuseppina Vitiello, Ratna Tripathy, Thomas Gstrein, Gaetano Terrone, Alex R. Paciorkowski, Maria Christina Sergaki, Alessandra D'Amico, Susan M. Hiatt, Ines Leca, Janneke Weiss, Ellyn Farrelly, Alistair T. Pagnamenta, Jenny C. Taylor, Nicola Brunetti-Pierri, David A. Keays, Tripathy, Ratna, Leca, Ine, van Dijk, Tessa, Weiss, Janneke, van Bon, Bregje W, Sergaki, Maria Christina, Gstrein, Thoma, Breuss, Martin, Tian, Guoling, Bahi-Buisson, Nadia, Paciorkowski, Alexander R, Pagnamenta, Alistair T, Wenninger-Weinzierl, Andrea, Martinez-Reza, Maria Fernanda, Landler, Luka, DE LISE, Stefano, Taylor, Jenny C, Terrone, Gaetano, Vitiello, Giuseppina, Del Giudice, Ennio, Brunetti-Pierri, Nicola, D'Amico, Alessandra, Reymond, Alexandre, Voisin, Norine, Bernstein, Jonathan A, Farrelly, Ellyn, Kini, Usha, Leonard, Thomas A, Valence, Stéphanie, Burglen, Lydie, Armstrong, Linlea, Hiatt, Susan M, Cooper, Gregory M, Aldinger, Kimberly A, Dobyns, William B, Mirzaa, Ghayda, Pierson, Tyler Mark, Baas, Frank, Chelly, Jamel, Cowan, Nicholas J, and Keays, David Anthony
- Subjects
0301 basic medicine ,Male ,Microcephaly ,Pathology ,PAX6 Transcription Factor ,Developmental Disabilities ,Apoptosis ,Corpus callosum ,Inbred C57BL ,AKT3 ,corpus callosum ,Mice ,Cerebellum ,2.1 Biological and endogenous factors ,Psychology ,Developmental ,Megalencephaly ,Aetiology ,Child ,Cells, Cultured ,Mice, Knockout ,Pediatric ,Cultured ,General Neuroscience ,Gene Expression Regulation, Developmental ,Brain ,Phenotype ,Malformations of Cortical Development ,Embryo ,Neurological ,Female ,MAST1 ,Cognitive Sciences ,Microtubule-Associated Proteins ,Rare cancers Radboud Institute for Health Sciences [Radboudumc 9] ,medicine.medical_specialty ,cerebellar hypoplasia ,Cells ,Knockout ,Intellectual and Developmental Disabilities (IDD) ,Nerve Tissue Proteins ,Biology ,Nervous System Malformations ,Article ,microtubules ,03 medical and health sciences ,Rare Diseases ,All institutes and research themes of the Radboud University Medical Center ,medicine ,Genetics ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,Neurology & Neurosurgery ,Animal ,Mammalian ,Neurosciences ,medicine.disease ,Embryo, Mammalian ,Newborn ,Brain Disorders ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,Animals, Newborn ,Gene Expression Regulation ,Disease Models ,Mutation ,Autism ,Congenital Structural Anomalies ,Cerebellar hypoplasia (non-human) ,Agenesis of Corpus Callosum ,microdeletion - Abstract
Corpus callosum malformations are associated with a broad range of neurodevelopmental diseases. We report that de novo mutations in MAST1 cause mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations (MCC-CH-CM) in the absence of megalencephaly. We show that MAST1 is a microtubule associated protein, that is predominantly expressed in post-mitotic neurons, and is present in both dendritic and axonal compartments. We further show that Mast1 null animals are phenotypically normal, whereas the deletion of a single amino acid (L278del) recapitulates the distinct neurological phenotype observed in patients. In animals harboring Mast1 microdeletions we find that the PI3K/AKT3/mTOR pathway is unperturbed, whereas Mast2 and Mast3 levels are diminished, indicative of a dominant negative mode of action. Finally, we report that de novo MAST1 substitutions are present in patients with autism and microcephaly, raising the prospect that mutations in this gene give rise to a spectrum of neurodevelopmental diseases.
- Published
- 2018
25. GeneYenta: A PhenotypeBased Rare Disease Case Matching Tool Based on Online Dating Algorithms for the Acceleration of Exome Interpretation
- Author
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Millan S. Patel, Wyeth W. Wasserman, Maja TarailoGraovac, Zachary D. Maurer, David J. Arenillas, Michael Gottlieb, Clara D.M. van Karnebeek, Linlea Armstrong, and Savanie Maithripala
- Subjects
Reference data ,Matching (statistics) ,Annotation ,Human Phenotype Ontology ,Genetics ,Ontology (information science) ,Biology ,Set (psychology) ,Exome ,Algorithm ,Genetics (clinical) ,Blossom algorithm - Abstract
Advances in next-generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontologybased semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching.
- Published
- 2015
26. Whole exome sequencing identifies aPOLRIDmutation segregating in a father and two daughters with findings of Klippel-Feil and Treacher Collins syndromes
- Author
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Alberto Santiago-Cornier, Robert D. Blank, Alexander Stoddard, David A. Sweetser, Michael A. Pickart, Enid Neptune, Nara Sobrera, Rachel Lorier, Philip F. Giampietro, Linlea Armstrong, Kristen Rasmussen, Amy Turner, Ulrich Broeckel, Sarah Sund, Cathy L. Raggio, and Janet Livingston
- Subjects
Male ,DNA Mutational Analysis ,Nuclear Family ,Fathers ,Chromosome Segregation ,Genetics ,Humans ,Medicine ,Missense mutation ,Exome ,Family ,Craniofacial ,Child ,Genetic Association Studies ,Genetics (clinical) ,Exome sequencing ,business.industry ,Genetic heterogeneity ,fungi ,Infant, Newborn ,Computational Biology ,DNA-Directed RNA Polymerases ,medicine.disease ,Hypoplasia ,Pedigree ,Klippel feil ,Klippel-Feil Syndrome ,Mutation ,Mutation (genetic algorithm) ,Female ,business ,Treacher Collins syndrome ,Mandibulofacial Dysostosis - Abstract
We report on a father and his two daughters diagnosed with Klippel–Feil syndrome (KFS) but with craniofacial differences (zygomatic and mandibular hypoplasia and cleft palate) and external ear abnormalities suggestive of Treacher Collins syndrome (TCS). The diagnosis of KFS was favored, given that the neck anomalies were the predominant manifestations, and that the diagnosis predated later recognition of the association between spinal segmentation abnormalities and TCS. Genetic heterogeneity and the rarity of large families with KFS have limited the ability to identify mutations by traditional methods. Whole exome sequencing identified a nonsynonymous mutation in POLR1D (subunit of RNA polymerase I and II): exon2:c.T332C:p.L111P. Mutations in POLR1D are present in about 5% of individuals diagnosed with TCS. We propose that this mutation is causal in this family, suggesting a pathogenetic link between KFS and TCS. © 2014 Wiley Periodicals, Inc.
- Published
- 2014
27. Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability
- Author
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Sylvie Langlois, Jill Mwenifumbo, Barbara M. McGillivray, Leora Lee, Steven J.M. Jones, Karen Mungall, Madeline Couse, Nancy Makela, Farah R. Zahir, Linlea Armstrong, Marco A. Marra, Cornelius F. Boerkoel, Emilia L. Lim, Jan M. Friedman, Hye Jung E. Chun, Clara D.M. van Karnebeek, Paediatric Metabolic Diseases, ANS - Cellular & Molecular Mechanisms, ANS - Compulsivity, Impulsivity & Attention, AGEM - Inborn errors of metabolism, ANS - Amsterdam Neuroscience, and AGEM - Amsterdam Gastroenterology Endocrinology Metabolism
- Subjects
0301 basic medicine ,SPRY4 ,lcsh:QH426-470 ,lcsh:Biotechnology ,PHF6 ,Mutation, Missense ,Sequence assembly ,Context (language use) ,Biology ,Genome ,Polymorphism, Single Nucleotide ,Structural variation ,03 medical and health sciences ,INDEL Mutation ,lcsh:TP248.13-248.65 ,Intellectual Disability ,Genetics ,Humans ,SQSTM1 ,Child ,1q43 microdeletion ,CACNB3 ,Exome sequencing ,Whole genome sequencing ,Genome assembly ,Genome, Human ,ARID1B ,3. Good health ,lcsh:Genetics ,030104 developmental biology ,UPF1 ,Human genome ,DNA microarray ,Biotechnology ,Research Article - Abstract
Background Intellectual Disability (ID) is among the most common global disorders, yet etiology is unknown in ~30% of patients despite clinical assessment. Whole genome sequencing (WGS) is able to interrogate the entire genome, providing potential to diagnose idiopathic patients. Methods We conducted WGS on eight children with idiopathic ID and brain structural defects, and their normal parents; carrying out an extensive data analyses, using standard and discovery approaches. Results We verified de novo pathogenic single nucleotide variants (SNV) in ARID1B c.1595delG and PHF6 c.820C > T, potentially causative de novo two base indels in SQSTM1 c.115_116delinsTA and UPF1 c.1576_1577delinsA, and de novo SNVs in CACNB3 c.1289G > A, and SPRY4 c.508 T > A, of uncertain significance. We report results from a large secondary control study of 2081 exomes probing the pathogenicity of the above genes. We analyzed structural variation by four different algorithms including de novo genome assembly. We confirmed a likely contributory 165 kb de novo heterozygous 1q43 microdeletion missed by clinical microarray. The de novo assembly resulted in unmasking hidden genome instability that was missed by standard re-alignment based algorithms. We also interrogated regulatory sequence variation for known and hypothesized ID genes and present useful strategies for WGS data analyses for non-coding variation. Conclusion This study provides an extensive analysis of WGS in the context of ID, providing genetic and structural insights into ID and yielding diagnoses. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3671-0) contains supplementary material, which is available to authorized users.
- Published
- 2017
28. De novo mutations in EBF3 cause a neurodevelopmental syndrome
- Author
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Alex Henderson, Vivienne McConnell, Helen Cox, Rita Horvath, Alex Magee, Jonathan H. Williams, Tanya N. Nelson, Mair E. A. Churchill, Andrew Green, James Hagman, Julia Rankin, Mary D. King, Caroline F. Wright, Hannah Sleven, Anna Lehman, Seth J. Welsh, Andrea H. Németh, Jing Yu, Julie Vogt, Penny Clouston, and Linlea Armstrong
- Subjects
0301 basic medicine ,Male ,Canada ,Ataxia ,Adolescent ,Developmental Disabilities ,Mutant ,Mutation, Missense ,Biology ,medicine.disease_cause ,03 medical and health sciences ,Report ,Intellectual Disability ,Intellectual disability ,Genetics ,medicine ,Missense mutation ,Humans ,Age of Onset ,Child ,Transcription factor ,Genetics (clinical) ,Mutation ,Cerebellar ataxia ,Infant, Newborn ,Infant ,DNA ,Syndrome ,medicine.disease ,Phenotype ,United Kingdom ,Strabismus ,030104 developmental biology ,Neurodevelopmental Disorders ,Face ,Female ,medicine.symptom ,Transcription Factors - Abstract
Early B cell factor 3 (EBF3) is an atypical transcription factor that is thought to influence the laminar formation of the cerebral cortex. Here, we report that de novo mutations in EBF3 cause a complex neurodevelopmental syndrome. The mutations were identified in two large-scale sequencing projects: the UK Deciphering Developmental Disorders (DDD) study and the Canadian Clinical Assessment of the Utility of Sequencing and Evaluation as a Service (CAUSES) study. The core phenotype includes moderate to severe intellectual disability, and many individuals exhibit cerebellar ataxia, subtle facial dysmorphism, strabismus, and vesicoureteric reflux, suggesting that EBF3 has a widespread developmental role. Pathogenic de novo variants identified in EBF3 include multiple loss-of-function and missense mutations. Structural modeling suggested that the missense mutations affect DNA binding. Functional analysis of mutant proteins with missense substitutions revealed reduced transcriptional activities and abilities to form heterodimers with wild-type EBF3. We conclude that EBF3, a transcription factor previously unknown to be associated with human disease, is important for brain and other organ development and warrants further investigation.
- Published
- 2017
29. Additional file 5: Supplementary Figures. of Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability
- Author
-
Zahir, Farah, Mwenifumbo, Jill, Chun, Hye-Jung, Lim, Emilia, Karnebeek, Clara Van, Couse, Madeline, Mungall, Karen, Lee, Leora, Makela, Nancy, Linlea Armstrong, Boerkoel, Cornelius, Langlois, Sylvie, McGillivray, Barbara, Jones, Steven, Friedman, Jan, and Marra, Marco
- Abstract
Figure S1. IGV image and Sanger verification trace files for indel in ARID1B and missense variation in UPF1. Figure S2. UK10K mutation load â counts as per variant annotation type on one patient. Figure S3. Histogram of mutation burden per patient in the UK10K cohort. Figure S4. Pathway interactions showing convergence onto UPP pathway. Figure S5. Plots for CNV distribution for two chromosomes as called by CNAseq. (DOCX 1972 kb)
- Published
- 2017
- Full Text
- View/download PDF
30. Additional file 1: of Comprehensive whole genome sequence analyses yields novel genetic and structural insights for Intellectual Disability
- Author
-
Zahir, Farah, Mwenifumbo, Jill, Chun, Hye-Jung, Lim, Emilia, Karnebeek, Clara Van, Couse, Madeline, Mungall, Karen, Lee, Leora, Makela, Nancy, Linlea Armstrong, Boerkoel, Cornelius, Langlois, Sylvie, McGillivray, Barbara, Jones, Steven, Friedman, Jan, and Marra, Marco
- Abstract
Supplementary Methods - Additional details on methods presented succinctly in main text. (DOCX 53 kb)
- Published
- 2017
- Full Text
- View/download PDF
31. Germline loss-of-function mutations in LZTR1 predispose to an inherited disorder of multiple schwannomas
- Author
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Christine Kobelka, Andrzej Poplawski, Alicia Gomes, David K. Crossman, Judith A. Westman, Michael R. Crowley, Jing Xie, Dusica Babovic-Vuksanovic, Stephanie Hurst, Pim Suwannarat, Bruce R. Korf, Molly S. Daniels, Andrea L Blumenthal, Chuanhua Fu, Piotr Madanecki, Ludwine Messiaen, Amanda L. Bergner, Rebecca Nagy, Linlea Armstrong, Katherine A. Rauen, Ying F Liu, Arkadiusz Piotrowski, Andrea Zanko, Jaishri O. Blakeley, Kathy Gardner, John M. Slopis, Howard Feit, and Chung Lee
- Subjects
Models, Molecular ,Neurofibromatosis 2 ,DNA, Complementary ,Chromosomal Proteins, Non-Histone ,Protein Conformation ,Chromosomes, Human, Pair 22 ,Molecular Sequence Data ,Loss of Heterozygosity ,Biology ,medicine.disease_cause ,Article ,Germline ,Loss of heterozygosity ,Germline mutation ,otorhinolaryngologic diseases ,Genetics ,medicine ,Humans ,Genetic Predisposition to Disease ,SMARCB1 ,Allele ,Schwannomatosis ,Germ-Line Mutation ,Loss function ,Genes, Dominant ,Mutation ,Base Sequence ,SMARCB1 Protein ,Sequence Analysis, DNA ,medicine.disease ,Pedigree ,DNA-Binding Proteins ,Gene Components ,Cancer research ,Neurilemmoma ,Microsatellite Repeats ,Transcription Factors - Abstract
Constitutional SMARCB1 mutations at 22q11.23 have been found in ~50% of familial and
- Published
- 2013
32. Approaches to Treating NF1 Tibial Pseudarthrosis
- Author
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B. Stephens Richards, Deborah M. Eastwood, Elizabeth K. Schorry, Mateusz Kolanczyk, Kim Hunter-Schaedle, Linlea Armstrong, David Wilkes, Feng Chun Yang, Gloria Gutierrez, David G. Little, Matthew E. Oetgen, Fergal Monsell, Florent Elefteriou, Tiziana Greggi, Aaron Schindeler, David L. Kendler, David Viskochil, David A. Stevenson, Alvin H. Crawford, and Jan M. Friedman
- Subjects
medicine.medical_specialty ,Consensus ,Neurofibromatosis 1 ,business.industry ,Nonunion ,General Medicine ,Bone healing ,medicine.disease ,Bone resorption ,Surgery ,Tibial Fractures ,Clinical trial ,Pseudarthrosis ,Dysplasia ,Pediatrics, Perinatology and Child Health ,Humans ,Medicine ,Orthopedics and Sports Medicine ,Tibia ,Neurofibromatosis ,Child ,business - Abstract
Background Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with various skeletal abnormalities occurring as part of a complex phenotype. Tibial dysplasia, which typically presents as anterolateral bowing of the leg with subsequent fracture and nonunion (pseudarthrosis), is a serious but infrequent osseous manifestation of NF1. Over the past several years, results from clinical and experimental studies have advanced our knowledge of the role of NF1 in bone. On the basis of current knowledge, we propose a number of concepts to consider as a theoretical approach to the optimal management of tibial pseudarthrosis. Methods A literature review for both clinical treatment and preclinical models for tibial dysplasia in NF1 was performed. Concepts were discussed and developed by experts who participated in the Children's Tumor Foundation sponsored International Bone Abnormalities Consortium meeting in 2011. Results Concepts for a theoretical approach to treating tibial pseudarthrosis include: bone fixation appropriate to achieve stability in any given case; debridement of the "fibrous pseudarthrosis tissue" between the bone segments associated with the pseudarthrosis; creating a healthy vascular bed for bone repair; promoting osteogenesis; controlling overactive bone resorption (catabolism); prevention of recurrence of the "fibrous pseudarthrosis tissue"; and achievement of long-term bone health to prevent recurrence. Conclusions Clinical trials are needed to assess effectiveness of the wide variation of surgical and pharmacologic approaches currently in practice for the treatment of tibial pseudarthrosis in NF1. Level of evidence Level V, expert opinion.
- Published
- 2013
33. The c.7409G>A (p.Cys2470Tyr) Variant of FBN1: Phenotypic Variability across Three Generations
- Author
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Y. Fan, D.J. Penny, S. Creighton, Patrice Eydoux, Linlea Armstrong, W. Duncan, William T. Gibson, and K.J. Potter
- Subjects
musculoskeletal diseases ,Genetics ,Marfan syndrome ,congenital, hereditary, and neonatal diseases and abnormalities ,business.industry ,Dural ectasia ,Bioinformatics ,medicine.disease ,Phenotype ,Exon ,Missense mutation ,Medicine ,business ,Gene ,Fibrillin ,Index case ,Genetics (clinical) - Abstract
Marfan syndrome is an autosomal dominant connective tissue disorder caused by mutations in the fibrillin gene FBN1, which encodes an extracellular matrix glycoprotein. Major features of Marfan syndrome occur in the ocular, cardiovascular, and skeletal systems as well as in the dura mater. Approximately 60% of known disease-causing mutations are missense mutations of single amino acid residues. Effects on the cardiovascular system are classically associated with mutations in exons 24-32 of the 65 FBN1 exons and many, though not all, reports associate missense mutations in exons 59-65 with a mild cardiovascular phenotype. Here we present 5 related individuals among whom a c.7409G>A (p.Cys2470Tyr) missense variant in exon 59 of FBN1 is associated with significant cardiovascular features. The index case also had an apparently de novo 46,XX,del(5)(q33.1q33.3) deletion on chromosome 5. This family demonstrates skeletal, dermatological and neurological features consistent with Marfan syndrome but lacks significant ophthalmological findings to date. These findings suggest that FBN1 C-terminal missense mutations may not confer the ophthalmological features of Marfan syndrome, but they also confer a more significant risk for cardiovascular pathology than that suggested by previous studies. Furthermore, clinical data from this family supports the previously reported association of dural ectasia with C-terminal mutations.
- Published
- 2013
34. Successful umbilical cord blood hematopoietic stem cell transplantation in pediatric patients with MDS/AML associated with underlying GATA2 mutations: two case reports and review of literature
- Author
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Kanwaldeep Mallhi, Jacob Rozmus, Linlea Armstrong, David Dix, and Karen Y. Niederhoffer
- Subjects
0301 basic medicine ,Oncology ,Male ,medicine.medical_specialty ,Myeloid ,Transplantation Conditioning ,Adolescent ,medicine.medical_treatment ,Cord Blood Stem Cell Transplantation ,Hematopoietic stem cell transplantation ,Haploinsufficiency ,Gene mutation ,Umbilical cord ,03 medical and health sciences ,0302 clinical medicine ,hemic and lymphatic diseases ,Internal medicine ,medicine ,Humans ,Child ,Transplantation ,business.industry ,Myelodysplastic syndromes ,Hematopoietic Stem Cell Transplantation ,medicine.disease ,GATA2 Transcription Factor ,Leukemia ,Leukemia, Myeloid, Acute ,030104 developmental biology ,medicine.anatomical_structure ,Treatment Outcome ,Myelodysplastic Syndromes ,Pediatrics, Perinatology and Child Health ,Mutation ,business ,030215 immunology - Abstract
Germline GATA2 mutations have been associated with a vast array of clinical manifestations, as well as hematological deficiencies and a propensity to AML or MDS. We present two cases of pediatric AML/MDS with underlying GATA2 mutations who underwent a successful umbilical cord hematopoietic stem cell transplantation using two different conditioning regimens. These cases illustrate the importance of recognizing the clinical features associated with GATA2 mutations and performing the appropriate molecular testing. Diagnosis of heritable gene mutations associated with familial AML/MDS has significant clinical implication for the patients and affected families.
- Published
- 2016
35. Exome Sequencing and the Management of Neurometabolic Disorders
- Author
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David S. Wishart, Bojana Rakic, Casper Shyr, Rupasri Mandal, Maja Tarailo-Graovac, Andre Mattman, Cristina Skrypnyk, Patrice Eydoux, Paul Shekel, Majid Alfadhel, Stuart E. Turvey, Janis M. Dionne, Hilary Vallance, Michelle Demos, A. Mark Evans, Colin J. D. Ross, Anna Lehman, Matthias R. Baumgartner, Jacob Rozmus, Bryan Sayson, Jan M. Friedman, Margaret L. McKinnon, Andrea Superti-Furga, Leo A. J. Kluijtmans, Britt I. Drögemöller, Kathryn Selby, Mary B. Connolly, Gabriella Horvath, Daniel Metzger, Kirk R. Schultz, John K. Wu, Ian Garber, Linlea Armstrong, Jessie M. Cameron, Ramona Salvarinova, Clara D.M. van Karnebeek, Dimitrios I. Zafeiriou, Jiqiang Ling, Ron A. Wevers, Lin Hua Zhang, Jiang Wu, Oluseye A. Ogunbayo, Graham Sinclair, Sylvia Stockler-Ipsiroglu, Suzanne M E Lewis, Margot I. Van Allen, Jessica J. Y. Lee, Wyeth W. Wasserman, Mena Abdelsayed, Peter C. Ruben, Patricie Burda, Aspasia Michoulas, Sandra Sirrs, Saikat Santra, Xin C. Ye, Tammie Dewan, Amit P. Bhavsar, and Other departments
- Subjects
0301 basic medicine ,Proband ,Adult ,Male ,Adolescent ,Genotype ,Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0] ,Bioinformatics ,03 medical and health sciences ,Young Adult ,Intellectual Disability ,Intellectual disability ,Medicine ,Humans ,Exome ,Genetic Testing ,Child ,Exome sequencing ,Genetic testing ,Genetics ,medicine.diagnostic_test ,business.industry ,Infant ,General Medicine ,Sequence Analysis, DNA ,Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3] ,medicine.disease ,Phenotype ,Developmental disorder ,030104 developmental biology ,Child, Preschool ,Female ,business ,Metabolism, Inborn Errors - Abstract
BACKGROUND: Whole-exome sequencing has transformed gene discovery and diagnosis in rare diseases. Translation into disease-modifying treatments is challenging, particularly for intellectual developmental disorder. However, the exception is inborn errors of metabolism, since many of these disorders are responsive to therapy that targets pathophysiological features at the molecular or cellular level.METHODS: To uncover the genetic basis of potentially treatable inborn errors of metabolism, we combined deep clinical phenotyping (the comprehensive characterization of the discrete components of a patient's clinical and biochemical phenotype) with whole-exome sequencing analysis through a semiautomated bioinformatics pipeline in consecutively enrolled patients with intellectual developmental disorder and unexplained metabolic phenotypes.RESULTS: We performed whole-exome sequencing on samples obtained from 47 probands. Of these patients, 6 were excluded, including 1 who withdrew from the study. The remaining 41 probands had been born to predominantly nonconsanguineous parents of European descent. In 37 probands, we identified variants in 2 genes newly implicated in disease, 9 candidate genes, 22 known genes with newly identified phenotypes, and 9 genes with expected phenotypes; in most of the genes, the variants were classified as either pathogenic or probably pathogenic. Complex phenotypes of patients in five families were explained by coexisting monogenic conditions. We obtained a diagnosis in 28 of 41 probands (68%) who were evaluated. A test of a targeted intervention was performed in 18 patients (44%).CONCLUSIONS: Deep phenotyping and whole-exome sequencing in 41 probands with intellectual developmental disorder and unexplained metabolic abnormalities led to a diagnosis in 68%, the identification of 11 candidate genes newly implicated in neurometabolic disease, and a change in treatment beyond genetic counseling in 44%. (Funded by BC Children's Hospital Foundation and others.).
- Published
- 2016
36. A girl with developmental delay, ataxia, cranial nerve palsies, severe respiratory problems in infancy-Expanding NDST1 syndrome
- Author
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Colin J. D. Ross, Maja Tarailo-Graovac, Wyeth W. Wasserman, Kimberly I. Seath, Linlea Armstrong, Graham Sinclair, Clara D.M. van Karnebeek, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, and Paediatric Metabolic Diseases
- Subjects
0301 basic medicine ,Pathology ,medicine.medical_specialty ,Ataxia ,Genotype ,Craniofacial abnormality ,Developmental Disabilities ,DNA Mutational Analysis ,Compound heterozygosity ,03 medical and health sciences ,Genetics ,medicine ,Humans ,Craniofacial ,Genetics (clinical) ,Exome sequencing ,Alleles ,Genetic Association Studies ,business.industry ,Cranial nerves ,Facies ,Syndrome ,medicine.disease ,Respiration Disorders ,Hypotonia ,Cranial Nerve Diseases ,3. Good health ,Pedigree ,Radiography ,030104 developmental biology ,Phenotype ,Child, Preschool ,Failure to thrive ,Mutation ,Female ,medicine.symptom ,Sulfotransferases ,business - Abstract
NDST1 encodes an enzyme involved in the first steps in the synthesis of heparan sulfate chains, proteoglycans that are regulators found on the cell surface and in the extracellular matrix. Eight individuals homozygous for one of four family-specific missense mutations in the sulfotransferase domain of the enzyme have been described. They have intellectual disability. Some additionally had hypotonia, ataxia. seizures, and/or short stature, but none had history of respiratory problems. No humans with homozygous null mutations are known. ndst1b (orthologous to NDST1) morpholino knockdown in zebrafish (Danio rerio) causes delayed development, craniofacial cartilage abnormalities, shortened body and pectoral fin length. Ndst1 homozygous null mice have craniofacial abnormalities and die within the first 10 h of life of respiratory failure. We report a girl upon whom deep phenotyping, extensive genetic and biochemical investigations, and exome sequencing were performed. She had cranial nerves dysfunction, gastroesophageal reflux, history of a seizure, ataxia, developmental delays, head sparing failure to thrive, and minor malformations including distinctive facial features and a bifid uvula. Compound heterozygous mutations in NDST1 were identified, in the heparan sulfate N deacetylatase domain of one allele and the sulfotransferase domain of the other allele. This report expands the phenotypic spectrum of Ndst1 deficiency in humans. © 2017 Wiley Periodicals, Inc.
- Published
- 2015
37. AIMP1 deficiency presents as a cortical neurodegenerative disease with infantile onset
- Author
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Wyeth W. Wasserman, Roberta Biancheri, Maja Tarailo-Graovac, Linlea Armstrong, C. J. Ross, C. van Karnebeek, Graham Sinclair, Andrea Rossi, Casper Shyr, and Other departments
- Subjects
Microcephaly ,Pathology ,medicine.medical_specialty ,Degenerative Disorder ,Biology ,Cellular and Molecular Neuroscience ,Epilepsy ,Myelin ,Genetics ,medicine ,Humans ,Genetics (clinical) ,Cerebral atrophy ,Age Factors ,Infant, Newborn ,Brain ,RNA-Binding Proteins ,Neurodegenerative Diseases ,medicine.disease ,White Matter ,Neoplasm Proteins ,Epileptic spasms ,medicine.anatomical_structure ,Mutation ,Cytokines ,Female ,Neuron ,Differential diagnosis - Abstract
We report the second family with AIMP1 deficiency, due to a homozygous truncating AIMP1 (g.107248613 C > T) mutation. This female showed early-onset developmental arrest, intractable epileptic spasms, microcephaly, and a rapid clinical course leading to premature death, associated with cerebral atrophy and myelin deficiency on brain MRI. Clinical and neuroimaging findings are consistent with a primary neuronal degenerative disorder, rather than with the previously reported Perlizaeus-Merzbacher-like phenotype. Given its critical role in neurofilament assembly 16, impaired myelin formation is due to neuronal/axonal dysfunction. We propose that AIMP1 deficiency be added to the differential diagnosis of infantile onset, progressive neurodegenerative disease.
- Published
- 2014
38. Abstract A190: Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology
- Author
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Janessa Laskin, Aly Karsan, Shahrad Rassekh, Jessica M T Nelson, Sean D. Young, Yaoqing Shen, Robyn Roscoe, Stephen Yip, Alexandra Fok, Martin K. Jones, Howard John Lim, Alice Virani, Linlea Armstrong, Kasmintan A. Schrader, Erin Pleasance, Marco A. Marra, and Rebecca Deyell
- Subjects
Oncology ,Whole genome sequencing ,Cancer Research ,medicine.medical_specialty ,business.industry ,Genomic research ,Genetic counseling ,Cancer ,Context (language use) ,Cancer Susceptibility Gene ,Oncogenomics ,medicine.disease ,Germline ,Internal medicine ,medicine ,business - Abstract
Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign, or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer-related information as part of the consent process for participation in the POG program. A subcommittee comprising medical geneticists, bioinformaticians, pathologists, oncologists, and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012-January 2017, 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, and 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high-penetrance mutations were already known to HCP. All VUS were reviewed by the subcommittee, taking into consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data were generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research-generated clinically relevant germline results to affected subjects. Citation Format: Howard J. Lim, Kasmintan A. Schrader, Sean Young, Jessica M T Nelson, Alexandra Fok, Erin Pleasance, Martin Jones, Yaoqing Shen, Linlea Armstrong, Alice Virani, Shahrad Rassekh, Rebecca Deyell, Stephen Yip, Robyn Roscoe, Aly Karsan, Marco Marra, Janessa J. Laskin. Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A190.
- Published
- 2018
39. Pre- and postnatal findings in a boy with duplication of the bladder and intestine: Report and review
- Author
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Kourosh Afshar, Majid Alfadhel, Ashley James Robinson, Christof Senger, Linlea Armstrong, James J. Murphy, and Denise Pugash
- Subjects
Adult ,Male ,medicine.medical_specialty ,medicine.medical_treatment ,Urinary Bladder ,Rectum ,Prenatal diagnosis ,urologic and male genital diseases ,Ultrasonography, Prenatal ,Pelvis ,Young Adult ,Fetus ,Ileum ,Pregnancy ,Prenatal Diagnosis ,Laparotomy ,Gene duplication ,Genetics ,medicine ,Humans ,Bladder duplication ,Genetics (clinical) ,Urinary bladder ,business.industry ,Infant, Newborn ,Anatomy ,Intestinal Duplication ,Intestines ,medicine.anatomical_structure ,Urethra ,Female ,Radiology ,business - Abstract
We describe a boy with a septated bladder and dilated bowel loop found on prenatal ultrasonography. Subsequent prenatal MRI diagnosed a probable caudal duplication anomaly. Postnatal investigations and surgical findings confirmed duplication of bladder, urethra, and bowel from distal ileum to rectum. This is the first reported case of combined bladder and colon duplication suspected antenatally with thorough imaging investigations including fetal MRI. While diagnosis of bladder duplication has been described, prenatal diagnosis of intestinal duplication has not been documented previously. This report of prenatal imaging with surgical and pathological correlation contributes to our detailed understanding of the spectrum of anatomy seen in caudal duplication anomaly.
- Published
- 2009
40. Skeletal abnormalities in neurofibromatosis type 1: Approaches to therapeutic options
- Author
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David L. Kendler, Gina Agiostratidou, Aaron Schindeler, Alvin H. Crawford, David Viskochil, Kim Hunter-Schaedle, Xijie Yu, David G. Little, John C. Carey, Patricia Birch, Elizabeth K. Schorry, Mateusz Kolanczyk, Feng Chun Yang, Linlea Armstrong, Stefan Mundlos, David A. Stevenson, Florent Elefteriou, David S. Feldman, Jan M. Friedman, Juha Peltonen, and Janet M. Hock
- Subjects
medicine.medical_specialty ,Neurofibromatosis 1 ,Disease ,Bioinformatics ,Key issues ,Models, Biological ,Bone and Bones ,Mice ,Internal medicine ,Sphenoid Bone ,Genetics ,medicine ,Animals ,Humans ,Neurofibromatosis ,Thoracic Wall ,Genetics (clinical) ,Bone Diseases, Developmental ,Developmental therapy ,Tibia ,business.industry ,medicine.disease ,Natural history ,Clinical trial ,Disease Models, Animal ,Endocrinology ,Skeletal abnormalities ,business - Abstract
The skeleton is frequently affected in individuals with neurofibromatosis type 1, and some of these bone manifestations can result in significant morbidity. The natural history and pathogenesis of the skeletal abnormalities of this disorder are poorly understood and consequently therapeutic options for these manifestations are currently limited. The Children's Tumor Foundation convened an International Neurofibromatosis Type 1 Bone Abnormalities Consortium to address future directions for clinical trials in skeletal abnormalities associated with this disorder. This report reviews the clinical skeletal manifestations and available preclinical mouse models and summarizes key issues that present barriers to optimal clinical management of skeletal abnormalities in neurofibromatosis type 1. These concepts should help advance optimal clinical management of the skeletal abnormalities in this disease and address major difficulties encountered for the design of clinical trials.
- Published
- 2009
41. Steroid sulfatase deficiency and contiguous gene deletion syndrome amongst pregnant patients with low serum unconjugated estriols
- Author
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Linlea Armstrong, Andre Mattman, Michelle Steinraths, Patricia Power, Janet Livingston, Gurdip Hulait, Kim Gall, Dawn Siciliano, Tanya N. Nelson, Denise Pugash, and Sylvie Langlois
- Subjects
medicine.medical_specialty ,Pregnancy ,Pediatrics ,X-linked ichthyosis ,Genetic counseling ,Incidence (epidemiology) ,Obstetrics and Gynecology ,Biology ,medicine.disease ,Contiguous gene syndrome ,Immunology ,medicine ,Steroid sulfatase ,Neonatology ,Family history ,Genetics (clinical) - Abstract
Objective To ascertain all prenatally diagnosed cases of Steroid Sulfatase (STS) deficiency in British Columbia between August 2002 and July 2007 to determine the incidence of this condition, the clinical and laboratory findings, and the risk of a contiguous gene deletion syndrome. Methods We reviewed the medical records of these patients to obtain detailed information about the maternal serum screening results, family history, investigations performed, and outcome of the pregnancy. Results Thirty pregnant patients were found to have a male fetus/infant with STS deficiency, giving a minimal estimated incidence of this condition of approximately 1 in 1513 males. In twenty nine cases, this condition was isolated. One patient was found to have a contiguous gene deletion syndrome. In cases of sporadic STS deficiency diagnosed prenatally, the frequency of contiguous gene deletion syndrome in this study was 1 out of 12 (8.3%). Conclusion The clinical, cytogenetic and molecular data on this series of prenatally diagnosed cases of STS deficiency indicates that this is a common condition and in cases with no family history, the risk of contiguous gene deletion syndrome is significant, and warrants additional molecular genetic investigations of the mother and/or fetus. Copyright © 2009 John Wiley & Sons, Ltd.
- Published
- 2009
42. The Identification of Lynch Syndrome in British Columbia
- Author
-
Linlea Armstrong, David G. Huntsman, Chris Bajdik, Carol Cremin, and Sharlene Gill
- Subjects
Adult ,Male ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Referral ,Base Pair Mismatch ,Genetic counseling ,Population ,Genetic Counseling ,Prevalence ,medicine ,Humans ,Genetic Testing ,lcsh:RC799-869 ,Medical History Taking ,education ,Early Detection of Cancer ,Germ-Line Mutation ,Adaptor Proteins, Signal Transducing ,Aged ,Genetic testing ,Genetics ,education.field_of_study ,British Columbia ,medicine.diagnostic_test ,business.industry ,Age Factors ,Gastroenterology ,Nuclear Proteins ,General Medicine ,Middle Aged ,medicine.disease ,Colorectal Neoplasms, Hereditary Nonpolyposis ,Lynch syndrome ,MutS Homolog 2 Protein ,Family medicine ,lcsh:Diseases of the digestive system. Gastroenterology ,Female ,Original Article ,Hereditary Cancer ,MutL Protein Homolog 1 ,business ,Program Evaluation - Abstract
OBJECTIVE: To determine the prevalence of Lynch syndrome mutations in a Canadian hereditary cancer clinic population, and to determine the effectiveness of the program’s referral criteria and testing algorithm.METHODS: A retrospective chart review of all patients who were referred for and received genetic counselling at the BC Cancer Agency’s Hereditary Cancer Program for a family history of colon cancer from August 1, 2004, to September 1, 2006, was performed. Charts were reviewed for referral criteria met, cancer history, whether testing was offered and the outcome of testing.RESULTS: Lynch syndrome was confirmed or highly suspected in 14.3% of index test patients (eight of 56) by the identification of a deleterious mutation or variant likely to be deleterious in either of thehMLH1orhMSH2mismatch repair genes. In the program, the two most effective criteria were a personal diagnosis of two or more primary Lynch syndrome-related cancers (one diagnosed at younger than 50 years of age) or two first-degree relatives with a Lynch syndrome-related cancer (both diagnosed at younger than 50 years of age). The respective positive predictive values of these two criteria were calculated to be 66.7% (95% CI 40% to 93%) and 58.3% (95% CI 30.4% to 86.2%).CONCLUSIONS: The Hereditary Cancer Program developed and successfully implemented an approach that selected individuals at risk for Lynch syndrome with a significant pretest probability of mutation of 14.3%. Improved ascertainment of families with Lynch syndrome will require greater physician awareness of referral criteria, program advances in the testing algorithm and a population-based approach to screening incident colon cancers.
- Published
- 2009
43. The use of anterolateral bowing of the lower leg in the diagnostic criteria for neurofibromatosis type 1
- Author
-
Alvin H. Crawford, David Viskochil, John C. Carey, Elizabeth K. Schorry, Jacques L. D’Astous, Linlea Armstrong, Kathleen A. Murray, David A. Stevenson, and Jan M. Friedman
- Subjects
musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,medicine.medical_specialty ,Neurofibromatosis 1 ,Medullary cavity ,Long bone ,Article ,Diagnosis, Differential ,medicine ,Humans ,Tibia ,Neurofibromatosis ,Genetics (clinical) ,Bone Diseases, Developmental ,business.industry ,Anatomy ,medicine.disease ,Radiography ,Pseudarthrosis ,medicine.anatomical_structure ,Dysplasia ,Radiology ,Ankle ,Differential diagnosis ,business - Abstract
Neurofibromatosis type 1 is diagnosed clinically based on the presence of two of seven criteria developed by a panel of experts in 1987. The sixth criterion focuses on skeletal findings and is as follows: "A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudarthrosis." The wording for this criterion is misleading. In particular, "thinning of long bone cortex" is not the characteristic radiographic presentation, and no mention of long bone bowing is included. The distinctive clinical feature of long bone dysplasia in neurofibromatosis type 1 is anterolateral bowing of the lower leg (portion of the body delimited by the knee and ankle). The usual radiographic findings of long bone dysplasia in neurofibromatosis type 1 at first presentation, prior to fracture, are anterolateral bowing with medullary canal narrowing and cortical thickening at the apex of the bowing. We suggest that anterolateral bowing of the lower leg, with or without fracture or pseudarthrosis, is a more appropriate description of the primary finding that a clinician will use to fulfill the sixth diagnostic criterion for neurofibromatosis type 1. Clarification of this diagnostic criterion is important for the clinician and for research protocols. Appropriate interpretation will improve understanding of the natural history and pathophysiology of neurofibromatosis type 1.
- Published
- 2007
44. Unrelated patients with a rearrangement of chromosome 2 causing duplication of 2p23 and deletion of 2q37
- Author
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David D. Weaver, Carole J. Bevan, Linlea Armstrong, Judith Allanson, and Holly H. Hobart
- Subjects
Male ,Monosomy ,Biology ,Frontal Bossing ,Gene Duplication ,Gene duplication ,Genetics ,medicine ,Humans ,Child ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,Chromosomal inversion ,Chromosome Aberrations ,Infant ,Chromosome ,medicine.disease ,Chromosome Banding ,Chromosomes, Human, Pair 2 ,Karyotyping ,Chromosome Inversion ,Female ,Sacral dimple ,Chromosome Deletion ,Abnormality ,Redundant nuchal skin - Abstract
We describe two unrelated patients who each have a similar chromosome 2 with duplication of 2p23 to pter, and deletion of 2q37 to qter. In one, the abnormality was derived from his mother with a pericentric inversion. Both individuals have frontal bossing; abnormally formed, low set and posteriorly rotated ears; redundant nuchal skin; inversion of the nipple(s); fleshy fingertips with prominent pads; a sacral dimple; significant developmental delay/mental retardation; and G-tube dependency. Most of these features are present in previously described individuals with either duplication of the 2p terminus or deletion of the 2q terminus. This report is the first that documents postnatal viability of individuals with concurrent duplication of 2p and deletion of 2q, and also generation of this imbalance through rearrangement of a maternally inherited pericentrically inverted 2. This report should be considered in the reproductive counseling of individuals with pericentric inversions of chromosome 2.
- Published
- 2005
45. Further delineation of Kabuki syndrome in 48 well-defined new individuals
- Author
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Stephen R. Braddock, Azza Abd El Moneim, Raoul C.M. Hennekam, Jeffrey E. Ming, Judith Allanson, Annick Raas-Rothschild, Dagmar Wieczorek, David J. Aughton, Alain Verloes, Karen W. Gripp, Theresa A. Grebe, Sarah M. Nikkel, Bryan D. Hall, Nicole Philip, Kirk Aleck, Annemarie Sommer, Nancy Mizue Kokitsu-Nakata, Linlea Armstrong, Alasdair G. W. Hunter, Clarisse Baumann, Claudia U. Walter, Gabriele Gillessen-Kaesbach, Angela E. Lin, John M. Graham, Elaine H. Zackai, Kim M. Keppler-Noreuil, Didier Lacombe, and Marc S. Williams
- Subjects
Genetics ,Pediatrics ,medicine.medical_specialty ,business.industry ,Paternal age ,medicine.disease ,Genetic etiology ,Popliteal pterygium syndrome ,Gene duplication ,medicine ,Etiology ,Van der Woude syndrome ,IRF6 ,business ,Kabuki syndrome ,Genetics (clinical) - Abstract
Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. This study of Kabuki syndrome had two objectives. The first was to further describe the syndrome features. In order to do so, clinical geneticists were asked to submit cases-providing clinical photographs and completing a phenotype questionnaire for individuals in whom they felt the diagnosis of Kabuki syndrome was secure. All submitted cases were reviewed by four diagnosticians familiar with Kabuki syndrome. The diagnosis was agreed upon in 48 previously unpublished individuals. Our data on these 48 individuals show that Kabuki syndrome variably affects the development and function of many organ systems. The second objective of the study was to explore possible etiological clues found in our data and from review of the literature. We discuss advanced paternal age, cytogenetic abnormalities, and familial cases, and explore syndromes with potentially informative overlapping features. We find support for a genetic etiology, with a probable autosomal dominant mode of inheritance, and speculate that there is involvement of the interferon regulatory factor 6 (IRF6) gene pathway. Very recently, a microduplication of 8p has been described in multiple affected individuals, the proportion of individuals with the duplication is yet to be determined.
- Published
- 2004
46. CCMG statement on gene patents
- Author
-
Jane A. Evans, Julie Richer, Tanya N. Nelson, Linlea Armstrong, Barbara McGillivray, and Julie Lauzon
- Subjects
Patents as Topic ,Genetics ,Canada ,Sequence Analysis, RNA ,Statement (logic) ,Philosophy ,Humans ,Human genome ,Genetic Testing ,Sequence Analysis, DNA ,Gene ,Genetics (clinical) - Abstract
Richer J, Nelson TN, Evans J, Armstrong L, Lauzon J, McGillivray B. CCMG statement on gene patents.
- Published
- 2012
47. De novo dup(X)(q22.3q26) in a girl with evidence that functional disomy of X material is the cause of her abnormal phenotype
- Author
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J E Allanson, Kathleen Brierley, Jean McGowan-Jordan, and Linlea Armstrong
- Subjects
Microcephaly ,medicine.medical_specialty ,Sex Chromosome Disorders ,Gonadal dysgenesis ,Biology ,Short stature ,Genetic determinism ,Gene Duplication ,Internal medicine ,Turner syndrome ,medicine ,Humans ,Child ,Sex Chromosome Aberrations ,Genetics (clinical) ,Chromosomes, Human, X ,medicine.disease ,Phenotype ,Chromosome Banding ,Developmental disorder ,Endocrinology ,Karyotyping ,dup ,Female ,medicine.symptom - Abstract
The relationship between phenotype and Xq duplications in females remains unclear. Some females are normal; some have short stature; and others have features such as microcephaly, developmental delay/mental retardation, body asymmetries, and gonadal dysgenesis. There are several hypotheses proposed in the literature to explain this variability. We describe a 7-year-old girl with dup(X)(q22.3q26). The pregnancy was complicated by intrauterine growth retardation, and she was distressed during labor. During her first year she fed poorly and failed to thrive. She has microcephaly, her height is at the 10th centile, and her hands and feet are strikingly small. She is hypotonic and delayed. Asymmetries of muscle power, and of leg and foot length have been noted. She has mild unilateral ptosis. She has some features of Turner syndrome, and multiple other minor anomalies such as flat labia. These are features common to other described females. This report describes our patient in detail and compares her phenotype to those of the other females with Xq duplications, displays our laboratory investigations, and discusses ideas regarding the pathogenesis of phenotype. The duplicated X is of paternal origin. It is inactivated in all cells; however, the distal duplicated portion appears to be active. We suggest that functional disomy of the duplicated X material, due to local escape from inactivation, may be responsible for the phenotype in the affected females.
- Published
- 2002
48. Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology
- Author
-
Janessa Laskin, Robyn Roscoe, Rebecca J. Deyell, Erin Pleasance, Yaoqing Shen, Aly Karsan, Alice Virani, Howard John Lim, Alexandra Fok, Stephen Yip, Linlea Armstrong, Jessica M T Nelson, Shahrad Rod Rassekh, Sean D. Young, Martin K. Jones, Marco A. Marra, and Kasmintan A. Schrader
- Subjects
Genetics ,Whole genome sequencing ,Cancer Research ,Oncology ,business.industry ,medicine ,Cancer ,Oncogenomics ,medicine.disease ,business ,Germline - Abstract
e13113 Background: The Personalized OncoGenomics (POG) project at the BC Cancer Agency utilizes tumor-normal whole genome sequencing (WGS) to understand key driver pathways and guide personalized treatment decisions. Analysis of the germline data can reveal variants; these may be presumed pathogenic, presumed benign or of unknown significance (VUS). We have developed a process for evaluating and returning presumed pathogenic variants in known cancer susceptibility genes to patients, for counseling and validation in a clinical-accredited laboratory. Methods: Patients receive germline cancer related information as part of the consent process for participation in the POG program. A sub-committee comprised of medical geneticists, bioinformaticians, pathologists, oncologists and an ethicist review the germline results. Any variants suspicious of being an artifact undergo a technical validation step. Presumed pathogenic findings of known cancer susceptibility genes are returned to the patient by their treating oncologist and patients are referred to the Hereditary Cancer Program (HCP), for genetic counseling and clinical confirmation. Results: From June 2012 - January 2017 – 466 patients have consented to the project. To date, 39 cases (8.4%) had at least one variant that was deemed pathogenic, 86 cases had at least one VUS in a known cancer susceptibility gene. 11 out of 23 cases (47.8%) with high penetrance mutations were already known to HCP. All VUS were reviewed by the sub-committee taking in to consideration the VUS and clinical context. 8 of the subjects with pathogenic results and 3 with VUS were known to HCP before POG data was generated. A VUS in 7 cases (1.5%) was returned after review. Conclusions: The number of pathogenic variants in known cancer susceptibility genes is consistent with published oncology results. We created a process to manage clinically relevant germline findings discovered during the course of genomic research to ensure appropriate care for patients. Genetic counseling within HCP and validation of variants in the clinically accredited Cancer Genetics Laboratory enables seamless return of research generated clinically relevant germline results to affected subjects. Clinical trial information: NCT02155621.
- Published
- 2017
49. GeneYenta: a phenotype-based rare disease case matching tool based on online dating algorithms for the acceleration of exome interpretation
- Author
-
Michael M, Gottlieb, David J, Arenillas, Savanie, Maithripala, Zachary D, Maurer, Maja, Tarailo Graovac, Linlea, Armstrong, Millan, Patel, Clara, van Karnebeek, and Wyeth W, Wasserman
- Subjects
Internet ,Gene Ontology ,Phenotype ,Rare Diseases ,Databases, Genetic ,Computational Biology ,High-Throughput Nucleotide Sequencing ,Humans ,Exome ,Algorithms ,Genetic Association Studies ,Software - Abstract
Advances in next-generation sequencing (NGS) technologies have helped reveal causal variants for genetic diseases. In order to establish causality, it is often necessary to compare genomes of unrelated individuals with similar disease phenotypes to identify common disrupted genes. When working with cases of rare genetic disorders, finding similar individuals can be extremely difficult. We introduce a web tool, GeneYenta, which facilitates the matchmaking process, allowing clinicians to coordinate detailed comparisons for phenotypically similar cases. Importantly, the system is focused on phenotype annotation, with explicit limitations on highly confidential data that create barriers to participation. The procedure for matching of patient phenotypes, inspired by online dating services, uses an ontology-based semantic case matching algorithm with attribute weighting. We evaluate the capacity of the system using a curated reference data set and 19 clinician entered cases comparing four matching algorithms. We find that the inclusion of clinician weights can augment phenotype matching.
- Published
- 2014
50. 232 Management of germline findings revealed throughout the course of tumor-normal whole genome sequencing in oncology
- Author
-
Erin Pleasance, Linlea Armstrong, Alexandra Fok, Martin Jones, Stephen Yip, Shahrad Rod Rassekh, Janessa Laskin, Rebecca J. Deyell, Howard John Lim, Aly Karsan, Robyn Roscoe, S. Young, Alice Virani, Kasmintan A. Schrader, Marco A. Marra, and Y. Shen
- Subjects
Genetics ,Whole genome sequencing ,Cancer Research ,Oncology ,Biology ,Germline - Published
- 2015
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