University of Oulu

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.

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;
Coban Akdemir, Zeynep6; Aleck, Kyrieckos A.7; Antaki, Danny8,9; Al Sharhan, Hind10,11; Au, Ping-Yee B.12; Aydin, Hatip13; Beggs, Alan H.4,5; Bilguvar, Kaya14,15; Boerwinkle, Eric16; Brand, Harrison3,17,18; Brownstein, Catherine A.4,5; Buyske, Steve19; Chodirker, Bernard20; Choi, Jungmin14,21; Chudley, Albert E.20; Clericuzio, Carol L.22; Cox, Gerald F.4,5; Curry, Cynthia23,24; De Boer, Elke25; De Vries, Bert B. A.25,26; Dunn, Kathryn5; Dutmer, Cullen M.27; England, Eleina M.3; Fahrner, Jill A.10; Geckinli, Bilgen B.28; Genetti, Casie A.4,5; Gezdirici, Alper29; Gibson, William T.30; Gleeson, Joseph G.8,9; Greenberg, Cheryl R.20; Hall, April31; Hamosh, Ada10; Hartley, Taila2; Jhangiani, Shalini N.6; Karaca, Ender6; Kernohan, Kristin2; Lauzon, Julie L.12; Lewis, M. E. Suzanne30; Lowry, R. Brian12; López-Giráldez, Francesc14,15; Matise, Tara C.32; McEvoy-Venneri, Jennifer8,9; McInnes, Brenda12; Mhanni, Aziz20; Garcia Minaur, Sixto33; Moilanen, Jukka34; Nguyen, An8,9; Nowaczyk, Malgorzata J. M.35; Posey, Jennifer E.6; Õunap, Katrin36,37; Pehlivan, Davut6,38,39; Pajusalu, Sander14,36,37; Penney, Lynette S.40; Poterba, Timothy3,41; Prontera, Paolo42; Rodovalho Doriqui, Maria Juliana43; Sawyer, Sarah L.1,2; Sobreira, Nara10; Stanley, Valentina8,9; Torun, Deniz44; Wargowski, David45; Witmer, P. Dane10; Wong, Isaac3,17,18; Xing, Jinchuan32; Zaki, Maha S.46; Zhang, Yeting32; Care4Rare Consortium2; Centers For Mendelian Genomics; Boycott, Kym M.1,2; Bamshad, Michael J.47,48,49; Nickerson, Deborah A.49,48; Blue, Elizabeth E.50; Innes, A. Micheil12
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:
Language: English
Published: John Wiley & Sons, 2021
Publish Date: 2023-01-23


Dubowitz 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.

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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
Type of Publication: A1 Journal article – refereed
Field of Science: 3111 Biomedicine
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 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.