DNA Polymerase epsilon deficiency causes IMAGe Syndrome with variable immunodeficiency

Clare Logan, Jennie Murray, David Parry, Andrea Robertson, Roberto Bellelli, Zygimante Tarnauskaite, Rachel Challis, Louise Cleal, Valerie Borel, Adeline Fluteau, Javier Santoyo-Lopez, SGP Consortium, Timothy Aitman, Ines Barroso, Donald Basel, L. Bicknell, Himanshu Goel, Hao Hu, Chad Huff, Michele HutchisonCaroline 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, Martin Reijns, Michael B Bober, Robert Semple, Simon J Boulton, Jonathan J Rios, Andrew Jackson, Andrea Robertson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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


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