2. Academic Validation
  3. WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features

WDR26 Haploinsufficiency Causes a Recognizable Syndrome of Intellectual Disability, Seizures, Abnormal Gait, and Distinctive Facial Features

  • Am J Hum Genet. 2017 Jul 6;101(1):139-148. doi: 10.1016/j.ajhg.2017.06.002.
Cara M Skraban 1,  Constance F Wells 2,  Preetha Markose 3,  Megan T Cho 4,  Addie I Nesbitt 5,  P Y Billie Au 6,  Amber Begtrup 4,  John A Bernat 7,  Lynne M Bird 8,  Kajia Cao 5,  Arjan P M de Brouwer 9,  Elizabeth H Denenberg 5,  Ganka Douglas 4,  Kristin M Gibson 5,  Katheryn Grand 3,  Alice Goldenberg 10,  A Micheil Innes 6,  Jane Juusola 4,  Marlies Kempers 11,  Esther Kinning 12,  David M Markie 13,  Martina M Owens 14,  Katelyn Payne 15,  Richard Person 4,  Rolph Pfundt 11,  Amber Stocco 16,  Claire L S Turner 17,  Nienke E Verbeek 18,  Laurence E Walsh 15,  Taylor C Warner 7,  Patricia G Wheeler 19,  Dagmar Wieczorek 20,  Alisha B Wilkens 21,  Evelien Zonneveld-Huijssoon 18,  Deciphering Developmental Disorders Study 22,  Tjitske Kleefstra 9,  Stephen P Robertson 2,  Avni Santani 23,  Koen L I van Gassen 18,  Matthew A Deardorff 24
Affiliations

Affiliations

  • 1 Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 2 Clinical Genetics Group, Department of Women's & Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • 3 Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
  • 4 GeneDx, Gaithersburg, MD 20877, USA.
  • 5 Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA.
  • 6 Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N1N4, Canada.
  • 7 Division of Medical Genetics, Stead Family Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA.
  • 8 Department of Pediatrics, University of California, San Diego and Rady Children's Hospital, San Diego, CA 92123, USA.
  • 9 Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands; Donders Institute for Brain, Cognition, and Behaviour, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
  • 10 Service de Génétique, Centre Hospitalier Universitaire de Rouen, Centre Normand de Génomique Médicale et Médecine Personnalisée, 76031 Rouen, France.
  • 11 Department of Human Genetics, Radboud University Medical Centre, 6500 HB Nijmegen, the Netherlands.
  • 12 West of Scotland Genetics Service, Queen Elizabeth Hospitals, Glasgow, Scotland G51 4TF, UK.
  • 13 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9054, New Zealand.
  • 14 Molecular Genetics Department, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK.
  • 15 Division of Child Neurology, Riley Hospital for Children, Indiana University Health Physicians, Indianapolis, IN 46202, USA.
  • 16 INTEGRIS Baptist Child Neurology Clinic, Oklahoma City, OK 73112, USA.
  • 17 Peninsula Clinical Genetics Service, Royal Devon and Exeter Hospital, Exeter EX1 2ED, UK.
  • 18 Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
  • 19 Division of Genetics, Arnold Palmer Hospital, Orlando, FL 32806, USA.
  • 20 Institut für Humangenetik, Universitätsklinikum Düsseldorf, Heinrich-Heine-Universität, 40225 Düsseldorf, Germany.
  • 21 Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA.
  • 22 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
  • 23 Division of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, 19104 USA; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104 USA.
  • 24 Division of Genetics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].
PMID: 28686853 DOI: 10.1016/j.ajhg.2017.06.002
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.

Keywords

WD-40; WDR protein; WDR26; intellectual disability; seizure.

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