2. Academic Validation
  3. DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency

  • Am J Hum Genet. 2018 Dec 6;103(6):1038-1044. doi: 10.1016/j.ajhg.2018.10.024.
Clare V Logan 1,  Jennie E Murray 2,  David A Parry 1,  Andrea Robertson 1,  Roberto Bellelli 3,  Žygimantė Tarnauskaitė 1,  Rachel Challis 4,  Louise Cleal 4,  Valerie Borel 3,  Adeline Fluteau 1,  Javier Santoyo-Lopez 5,  SGP Consortium,  Tim Aitman 6,  Inês Barroso 7,  Donald Basel 8,  Louise S Bicknell 9,  Himanshu Goel 10,  Hao Hu 11,  Chad Huff 11,  Michele Hutchison 12,  Caroline Joyce 13,  Rachel Knox 14,  Amy E Lacroix 15,  Sylvie Langlois 16,  Shawn McCandless 17,  Julie McCarrier 8,  Kay A Metcalfe 18,  Rose Morrissey 19,  Nuala Murphy 20,  Irène Netchine 21,  Susan M O'Connell 20,  Ann Haskins Olney 15,  Nandina Paria 22,  Jill A Rosenfeld 23,  Mark Sherlock 24,  Erin Syverson 8,  Perrin C White 25,  Carol Wise 26,  Yao Yu 11,  Margaret Zacharin 27,  Indraneel Banerjee 28,  Martin Reijns 1,  Michael B Bober 29,  Robert K Semple 30,  Simon J Boulton 3,  Jonathan J Rios 26,  Andrew P Jackson 31
Affiliations

Affiliations

  • 1 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • 2 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; South East Scotland Clinical Genetics Service, Western General Hospital, Edinburgh EH4 2XU, UK. Electronic address: [email protected].
  • 3 The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
  • 4 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK; South East Scotland Clinical Genetics Service, Western General Hospital, Edinburgh EH4 2XU, UK.
  • 5 Edinburgh Genomics Clinical Division, University of Edinburgh, The Roslin Institute, Edinburgh EH25 9RG, UK.
  • 6 MRC Centre for Genomic & Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • 7 Wellcome Sanger Institute, Cambridge CB10 1SA, UK.
  • 8 Medical College of Wisconsin from Children's Hospital of Wisconsin, Milwaukee, WI 53226, USA.
  • 9 Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.
  • 10 Hunter Genetics, Waratah, NSW 2305, Australia; University of Newcastle, Callaghan, NSW 2308, Australia.
  • 11 Department of Epidemiology, MD Anderson Cancer Center, Houston, TX 77030, USA.
  • 12 Department of Pediatrics, University of Arkansas, Little Rock, AR 72205, USA.
  • 13 Department of Clinical Biochemistry, Cork University Hospital, Cork, Ireland.
  • 14 MRC Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK.
  • 15 University of Nebraska Medical Centre, Omaha, NE 68918, USA.
  • 16 Department of Medical Genetics, The University of British Columbia, Vancouver, BC V6H 3N1, Canada.
  • 17 Pediatric Genetics, UH Cleveland Medical Center, Cleveland, OH 44106, USA.
  • 18 Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust and Institute of Human Development, University of Manchester, Manchester M13 9WL, UK.
  • 19 Department of Paediatrics and Child Health, Cork University Hospital, Cork, Ireland.
  • 20 UCD School of Medicine, Children's University Hospital, Temple St, Dublin, Ireland.
  • 21 Sorbonne Université, INSERM, UMR_S 938, APHP, Hospital Trousseau, 75012 Paris, France.
  • 22 Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA.
  • 23 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 24 Department of Endocrinology, Beaumont Hospital, Dublin, Ireland.
  • 25 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 26 Sarah M. and Charles E. Seay Center for Musculoskeletal Research, Texas Scottish Rite Hospital for Children, Dallas, TX 75219, USA; Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Orthopaedic Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
  • 27 Division of Medicine, Royal Children's Hospital, Melbourne, VIC 3052, Australia.
  • 28 Department of Paediatric Endocrinology, Royal Manchester Children's Hospital, Manchester Academic Health Science Centre, Manchester M13 9WU, UK.
  • 29 Nemours-Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA.
  • 30 MRC Metabolic Diseases Unit, University of Cambridge, Cambridge CB2 0QQ, UK; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK.
  • 31 MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK. Electronic address: [email protected].
PMID: 30503519 DOI: 10.1016/j.ajhg.2018.10.024
Abstract

During genome replication, polymerase epsilon (Pol ε) acts as the major leading-strand DNA polymerase. Here we report the identification of biallelic mutations in POLE, encoding the Pol ε catalytic subunit POLE1, in 15 individuals from 12 families. Phenotypically, these individuals had clinical features closely resembling IMAGe syndrome (intrauterine growth restriction [IUGR], metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. POLE1-deficient individuals also exhibited distinctive facial features and variable immune dysfunction with evidence of lymphocyte deficiency. All subjects shared the same intronic variant (c.1686+32C>G) as part of a common haplotype, in combination with different loss-of-function variants in trans. The intronic variant alters splicing, and together the biallelic mutations lead to cellular deficiency of Pol ε and delayed S-phase progression. In summary, we establish POLE as a second gene in which mutations cause IMAGe syndrome. These findings add to a growing list of disorders due to mutations in DNA replication genes that manifest growth restriction alongside adrenal dysfunction and/or immunodeficiency, consolidating these as replisome phenotypes and highlighting a need for future studies to understand the tissue-specific development roles of the encoded proteins.

Keywords

DNA replication; IMAGe syndrome; adrenal failure; cell cycle; growth; immunodeficiency; microcephaly; polymerase epsilon.

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