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DNA Polymerase epsilon deficiency causes IMAGe Syndrome with variable immunodeficiency

Research output: Contribution to journalArticle

  • Andrea Robertson
  • Roberto Bellelli
  • Zygimante Tarnauskaite
  • Louise Cleal
  • Valerie Borel
  • Adeline Fluteau
  • J. Santoyo-Lopez
  • SGP Consortium
  • Ines Barroso
  • Donald Basel
  • L. Bicknell
  • Himanshu Goel
  • Hao Hu
  • Chad Huff
  • Michele Hutchison
  • Caroline Joyce
  • Rachel Knox
  • Sylvie Langlois
  • Shawn McCandless
  • Julie McCarrier
  • Rose Morrissey
  • Nuala Murphy
  • Irene Netchine
  • Susan M O'Connell
  • Ann Haskins Olney
  • Nandina Paria
  • Jill A Rosenfeld
  • Mark Sherlock
  • Erin Syverson
  • P White
  • Carol Wise
  • Yao Yu
  • Margaret Zacharin
  • Indraneel Banerjee
  • Michael B Bober
  • Simon J Boulton
  • Jonathan J Rios

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Original languageEnglish
Pages (from-to)1038-1044
JournalAmerican Journal of Human Genetics
Issue number6
Early online date29 Nov 2018
Publication statusPublished - 6 Dec 2018


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.

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