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Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome |
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| Author: | Dyment, David A.1,2; O'Donnell-Luria, Anne3,4,5; Agrawal, Pankaj B.4,5; |
| Organizations: |
1Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada 2Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada 3Broad Institute of MIT and Harvard, Broad Center for Mendelian Genomics, Cambridge, Massachusetts, USA
4Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA
5The Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, Massachusetts, USA 6Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA 7Department of Genetics and Metabolism, Phoenix Children's Medical Group, Phoenix, Arizona, USA 8Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, California, USA 9Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, California, USA 10McKusick-Nathans Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA 11Department of Pediatrics, Faculty of Medicine, Kuwait University, Kuwait City, Kuwait 12Department of Medical Genetics and Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada 13Centre of Genetics Diagnosis, Zeynep Kamil Maternity and Children's Training and Research Hospital, Istanbul, Turkey 14Department of Genetics, Yale School of Medicine, New Haven, Connecticut, USA 15Yale Center for Genome Analysis, Yale School of Medicine, New Haven, Connecticut, USA 16Human Genome Sequencing Center, Baylor College of Medicine, Waco, Texas, USA 17Center for Genomic Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA 18Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA 19Department of Statistics and Biostatistics, Rutgers University, Piscataway, New Jersey, USA 20Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, Manitoba, Canada 21Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea 22Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA 23University of California, San Francisco, California, USA 24Genetic Medicine, University Pediatric Specialists, Fresno, California, USA 25Department of Human Genetics, Raboud University Medical Centre, Nijmegen, Netherlands 26Donders Institute for Brain, Cognition and Behaviour, Raboud University Medical Centre, Nijmegen, Netherlands 27Children's Hospital Colorado and University of Colorado School of Medicine, Aurora, Colorado, USA 28Department of Medical Genetics, School of Medicine, Marmara University, Istanbul, Turkey 29Department of Medical Genetics, Kanuni Sultan Suleyman Training and Research Hospital, Istanbul, Turkey 30Department of Medical Genetics and British Columbia Children's Hospital Research Institute, University of British Columbia, Vancouver, British Columbia, Canada 31Waisman Center Clinical Genetics, University of Wisconsin, Madison, Wisconsin, USA 32Department of Genetics, Human Genetics Institute of New Jersey, Rutgers University, Piscataway, New Jersey, USA 33Sección de Genética Clínica, INGEMM (Instituto de Genética Médica y Molecular), Madrid, Spain 34Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Unit, University of Oulu, Oulu, Finland 35Department of Pathology and Molecular Medicine, McMaster University, Hamilton, Ontario, Canada 36United Laboratories, Department of Clinical Genetics, Tartu University Hospital, Tartu, Estonia 37Institute of Clinical Medicine, Department of Clinical Genetics, Tartu University Hospital, Tartu, Estonia 38Texas Children's Hospital, Houston, Texas, USA 39Section of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA 40Department of Pediatrics, IWK Health Centre, Dalhousie University, Halifax, Nova Scotia, Canada 41Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA 42Medical Genetics Unit, Hospital Santa Maria della Misericordia and University of Perugia, Perugia, Italy 43Complexo Hospitalar Materno Infantil do MA – Matern, Benedito Leite e Hospital Infantil Juvencio Mattos, Sao Luis, Brazil 44Department of Medical Genetics, Gulhane Military Medical Academy, Ankara, Turkey 45Division of Genetics, Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA 46Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt 47Department of Pediatrics, University of Washington, Seattle, Washington, USA 48Department of Genome Sciences, University of Washington, Seattle, Washington, USA 49Brotman-Baty Institute for Precision Medicine, Seattle, Washington, USA 50Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, Washington, USA |
| Format: | article |
| Version: | accepted version |
| Access: | open |
| Online Access: | PDF Full Text (PDF, 1.5 MB) |
| Persistent link: | http://urn.fi/urn:nbn:fi-fe202301235225 |
| Language: | English |
| Published: |
John Wiley & Sons,
2021
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| Publish Date: | 2023-01-23 |
| Description: |
AbstractDubowitz syndrome (DubS) is considered a recognizable syndrome characterized by a distinctive facial appearance and deficits in growth and development. There have been over 200 individuals reported with Dubowitz or a “Dubowitz-like” condition, although no single gene has been implicated as responsible for its cause. We have performed exome (ES) or genome sequencing (GS) for 31 individuals clinically diagnosed with DubS. After genome-wide sequencing, rare variant filtering and computational and Mendelian genomic analyses, a presumptive molecular diagnosis was made in 13/27 (48%) families. The molecular diagnoses included biallelic variants in SKIV2L, SLC35C1, BRCA1, NSUN2; de novo variants in ARID1B, ARID1A, CREBBP, POGZ, TAF1, HDAC8, and copy-number variation at1p36.11(ARID1A), 8q22.2(VPS13B), Xp22, and Xq13(HDAC8). Variants of unknown significance in known disease genes, and also in genes of uncertain significance, were observed in 7/27 (26%) additional families. Only one gene, HDAC8, could explain the phenotype in more than one family (N = 2). All but two of the genomic diagnoses were for genes discovered, or for conditions recognized, since the introduction of next-generation sequencing. Overall, the DubS-like clinical phenotype is associated with extensive locus heterogeneity and the molecular diagnoses made are for emerging clinical conditions sharing characteristic features that overlap the DubS phenotype. see all
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| Series: |
American journal of medical genetics. Part A |
| ISSN: | 1552-4825 |
| ISSN-E: | 1552-4833 |
| ISSN-L: | 1552-4825 |
| Pages: | 119 - 133 |
| DOI: | 10.1002/ajmg.a.61926 |
| OADOI: | https://oadoi.org/10.1002/ajmg.a.61926 |
| Type of Publication: |
A1 Journal article – refereed |
| Field of Science: |
3111 Biomedicine |
| Subjects: | |
| Funding: |
The Care4Rare Canada Consortium work was funded by Genome Canada and the Ontario Genomics Institute (OGI-147), the Canadian Institutes of Health Research, Ontario Research Fund, Genome Alberta, Genome British Columbia, Genome Quebec, and Children's Hospital of Eastern Ontario Foundation. Funding was also provided by the National Organization of Rare Disorders (NORD). The Baylor Hopkins Center for Mendelian Genomics, Broad Institute Harvard Center for Mendelian Genomics, University of Washington Center for Mendelian Genomics, and Yale Center for Mendelian Genomics were funded by the National Human Genome Research Institute (NHGRI)/National Heart Lung and Blood Institute (NHLBI)/National Eye Institute (NEI) awards UM1 HG006542, UM1 HG008900, UM1 HG006493, and UM1 HG006504, respectively. Analysis was additionally supported by NHGRI grant R01 HG009141. Funds were also provided under the NHLBI under the Trans-Omics for Precision Medicine Program (TOPMed). The GSP Coordinating Center (NHGRI U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. A. H. O.-L. was supported by National Institute of Child Health and Human Development (NICHD) K12 HD052896 and a Boston Children's Hospital OFD Career Development Award. J. E. P. was supported by NHGRI K08 HG008986. K. Õ. and S. P. are supported by Estonian Research Council grants PRG471 and PUTJD827. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was financially supported by grants from the Dutch Organization for Health Research and Development (ZON-MW grants 917-86-319 and 912-12-109 to B. B. A. d. V.). |
| Copyright information: |
© 2020 Wiley Periodicals LLC. This is the peer reviewed version of the following article: Dyment, DA, O'Donnell-Luria, A, Agrawal, PB, et al. Alternative genomic diagnoses for individuals with a clinical diagnosis of Dubowitz syndrome. Am J Med Genet Part A. 2021; 185A: 119– 133., which has been published in final form at https://doi.org/10.1002/ajmg.a.61926. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. This article may not be enhanced, enriched or otherwise transformed into a derivative work, without express permission from Wiley or by statutory rights under applicable legislation. Copyright notices must not be removed, obscured or modified. The article must be linked to Wiley’s version of record on Wiley Online Library and any embedding, framing or otherwise making available the article or pages thereof by third parties from platforms, services and websites other than Wiley Online Library must be prohibited. |