2. Academic Validation
  3. Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features

Missense Mutations of the Pro65 Residue of PCGF2 Cause a Recognizable Syndrome Associated with Craniofacial, Neurological, Cardiovascular, and Skeletal Features

  • Am J Hum Genet. 2018 Nov 1;103(5):786-793. doi: 10.1016/j.ajhg.2018.09.012.
Peter D Turnpenny 1,  Michael J Wright 2,  Melissa Sloman 3,  Richard Caswell 4,  Anthony J van Essen 5,  Erica Gerkes 5,  Rolph Pfundt 6,  Susan M White 7,  Nava Shaul-Lotan 8,  Lori Carpenter 9,  G Bradley Schaefer 10,  Alan Fryer 11,  A Micheil Innes 12,  Kirsten P Forbes 13,  Wendy K Chung 14,  Heather McLaughlin 15,  Lindsay B Henderson 15,  Amy E Roberts 16,  Karen E Heath 17,  Beatriz Paumard-Hernández 17,  Blanca Gener 18,  DDD study 19,  Katherine A Fawcett 20,  Romana Gjergja-Juraški 21,  Daniela T Pilz 22,  Andrew E Fry 23
Affiliations

Affiliations

  • 1 Peninsula Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX1 2ED, UK. Electronic address: peter.turnpenny@nhs.net.
  • 2 Northern Genetics Service, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle NE1 3BZ, UK.
  • 3 Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
  • 4 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX1 2LU, UK.
  • 5 Department of Genetics, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, the Netherlands.
  • 6 Human Genetics, Radboud University Nijmegen Medical Centre, 6525 GA Nijmegen, the Netherlands.
  • 7 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, Victoria 3052, Australia; Department of Paediatrics, University of Melbourne, Parkville, Victoria 3052, Australia.
  • 8 Clinical Genetics, Hadassah-Hebrew University Medical Center, Ein Kerem, Jerusalem 91120, Israel.
  • 9 Saint Francis Genetics, Tulsa, Oklahoma 74136, USA.
  • 10 University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
  • 11 Cheshire and Merseyside Clinical Genetic Service, Liverpool Women's NHS Foundation Trust, Liverpool L8 7SS, UK.
  • 12 Department of Medical Genetics and Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta T3B 6A8, Canada.
  • 13 Department of Neuroradiology, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
  • 14 Departments of Pediatrics and Medicine, Columbia University, New York, NY 10032, USA.
  • 15 GeneDx, Gaithersburg, Maryland 20877, USA.
  • 16 Cardiovascular Genetics, Department of Cardiology and Division of Genetics, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
  • 17 Institute of Medical & Molecular Genetics (INGEMM) and Skeletal Dysplasia Multidisciplinary Unit (UMDE), Hospital Universitario la Paz, Universidad Autónoma de Madrid, IdiPAZ, 28046 Madrid, Spain; Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCII), 28029 Madrid, Spain.
  • 18 Centro de Investigación Biomédica en Red Enfermedades Raras (CIBERER), Instituto de Salud Carlos III (ISCII), 28029 Madrid, Spain; Department of Genetics, Cruces University Hospital, Biocruces Health Research Institute, 48903 Barakaldo, Bizkaia, Spain.
  • 19 Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
  • 20 MRC Computational Genomics Analysis and Training Programme (CGAT), MRC Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
  • 21 Medical School of Osijek, Josip Juraj Strossmayer University, Neuropediatric Unit, Children's Hospital Srebrnjak, CRO-10000 Zagreb, Croatia.
  • 22 West of Scotland Genetic Services, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
  • 23 Institute of Medical Genetics, University Hospital of Wales, Cardiff CF14 4XW, UK; Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK. Electronic address: fryae@cardiff.ac.uk.
PMID: 30343942 DOI: 10.1016/j.ajhg.2018.09.012
Abstract

PCGF2 encodes the polycomb group ring finger 2 protein, a transcriptional repressor involved in cell proliferation, differentiation, and embryogenesis. PCGF2 is a component of the polycomb repressive complex 1 (PRC1), a multiprotein complex which controls gene silencing through histone modification and chromatin remodelling. We report the phenotypic characterization of 13 patients (11 unrelated individuals and a pair of monozygotic twins) with missense mutations in PCGF2. All the mutations affected the same highly conserved proline in PCGF2 and were de novo, excepting maternal mosaicism in one. The patients demonstrated a recognizable facial gestalt, intellectual disability, feeding problems, impaired growth, and a range of brain, cardiovascular, and skeletal abnormalities. Computer structural modeling suggests the substitutions alter an N-terminal loop of PCGF2 critical for histone biding. Mutant PCGF2 may have dominant-negative effects, sequestering PRC1 components into complexes that lack the ability to interact efficiently with histones. These findings demonstrate the important role of PCGF2 in human development and confirm that heterozygous substitutions of the Pro65 residue of PCGF2 cause a recognizable syndrome characterized by distinctive craniofacial, neurological, cardiovascular, and skeletal features.

Keywords

MEL18; PCGF2; Polycomb Group Ring Finger 2; dysmorphism; intellectual disability; polymicrogyria.

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