Journal article
WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features
American journal of human genetics, Vol.101(1), pp.139-148
07/06/2017
DOI: 10.1016/j.ajhg.2017.06.002
PMCID: PMC5501873
PMID: 28686853
Abstract
We report 15 individuals with de novo pathogenic variants in WDR26. Eleven of the individuals carry loss-of-function mutations, and four harbor missense substitutions. These 15 individuals comprise ten females and five males, and all have intellectual disability with delayed speech, a history of febrile and/or non-febrile seizures, and a wide-based, spastic, and/or stiff-legged gait. These subjects share a set of common facial features that include a prominent maxilla and upper lip that readily reveal the upper gingiva, widely spaced teeth, and a broad nasal tip. Together, these features comprise a recognizable facial phenotype. We compared these features with those of chromosome 1q41q42 microdeletion syndrome, which typically contains WDR26, and noted that clinical features are consistent between the two subsets, suggesting that haploinsufficiency of WDR26 contributes to the pathology of 1q41q42 microdeletion syndrome. Consistent with this, WDR26 loss-of-function single-nucleotide mutations identified in these subjects lead to nonsense-mediated decay with subsequent reduction of RNA expression and protein levels. We derived a structural model of WDR26 and note that missense variants identified in these individuals localize to highly conserved residues of this WD-40-repeat-containing protein. Given that WDR26 mutations have been identified in ∼1 in 2,000 of subjects in our clinical cohorts and that WDR26 might be poorly annotated in exome variant-interpretation pipelines, we would anticipate that this disorder could be more common than currently appreciated.
Details
- Title: Subtitle
- WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features
- Creators
- Cara M Skraban - Division of Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAConstance F Wells - Clinical Genetics Group, Department of Women’s & Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New ZealandPreetha Markose - Division of Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAMegan T Cho - GeneDx, Gaithersburg, MD 20877, USAAddie I Nesbitt - Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USAP.Y. Billie Au - Department of Medical Genetics and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N1N4, CanadaAmber Begtrup - GeneDx, Gaithersburg, MD 20877, USAJohn A Bernat - Division of Medical Genetics, Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USALynne M Bird - Department of Pediatrics, University of California, San Diego and Rady Children’s Hospital, San Diego, CA 92123, USAKajia Cao - Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USAArjan P.M de Brouwer - Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the NetherlandsElizabeth H Denenberg - Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USAGanka Douglas - GeneDx, Gaithersburg, MD 20877, USAKristin M Gibson - Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USAKatheryn Grand - Division of Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAAlice Goldenberg - Service de Génétique, Centre Hospitalier Universitaire de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, 76031 Rouen, FranceA. Micheil Innes - Department of Medical Genetics and Alberta Children’s Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N1N4, CanadaJane Juusola - GeneDx, Gaithersburg, MD 20877, USAMarlies Kempers - Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the NetherlandsEsther Kinning - West of Scotland Genetics Service, Queen Elizabeth Hospitals, Glasgow, Scotland G51 4TF, UKDavid M Markie - Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New ZealandMartina M Owens - Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UKKatelyn Payne - Division of Child Neurology, Riley Hospital for Children, Indiana University Health Physicians, Indianapolis, IN 46202, USARichard Person - GeneDx, Gaithersburg, MD 20877, USARolph Pfundt - Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the NetherlandsAmber Stocco - INTEGRIS Baptist Child Neurology Clinic, Oklahoma City, OK 73112, USAClaire L.S Turner - Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital, Exeter EX1 2ED, UKNienke E Verbeek - Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the NetherlandsLaurence E Walsh - Division of Child Neurology, Riley Hospital for Children, Indiana University Health Physicians, Indianapolis, IN 46202, USATaylor C Warner - Division of Medical Genetics, Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USAPatricia G Wheeler - Division of Genetics, Arnold Palmer Hospital, Orlando, FL 32806, USADagmar Wieczorek - Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, 40225 Düsseldorf, GermanyAlisha B Wilkens - Division of Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USAEvelien Zonneveld-Huijssoon - Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the NetherlandsTjitske Kleefstra - Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the NetherlandsStephen P Robertson - Clinical Genetics Group, Department of Women’s & Children’s Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New ZealandAvni Santani - Division of Genomic Diagnostics, Children’s Hospital of Philadelphia, Philadelphia, PA, 19104 USAKoen L.I van Gassen - Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the NetherlandsMatthew A Deardorff - Division of Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA 19104, USADeciphering Developmental Disorders Study
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.101(1), pp.139-148
- DOI
- 10.1016/j.ajhg.2017.06.002
- PMID
- 28686853
- PMCID
- PMC5501873
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 0002-9297
- eISSN
- 1537-6605
- Publisher
- Elsevier Inc
- Language
- English
- Date published
- 07/06/2017
- Academic Unit
- Stead Family Department of Pediatrics; Medical Genetics and Genomics
- Record Identifier
- 9984093455002771
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