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Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance

Author

Listed:
  • Kashyap A. Patel

    (University of Exeter Medical School)

  • Jarno Kettunen

    (Helsinki University Hospital
    University of Helsinki
    University of Helsinki)

  • Markku Laakso

    (Kuopio University Hospital
    University of Eastern Finland)

  • Alena Stančáková

    (University of Eastern Finland)

  • Thomas W. Laver

    (University of Exeter Medical School)

  • Kevin Colclough

    (Royal Devon and Exeter National Health Service Foundation Trust)

  • Matthew B. Johnson

    (University of Exeter Medical School)

  • Marc Abramowicz

    (Université Libre de Bruxelles)

  • Leif Groop

    (Lund University, Skåne University Hospital
    University of Helsinki)

  • Päivi J. Miettinen

    (University of Helsinki and Helsinki University Hospital
    University of Helsinki)

  • Maggie H. Shepherd

    (University of Exeter Medical School)

  • Sarah E. Flanagan

    (University of Exeter Medical School)

  • Sian Ellard

    (University of Exeter Medical School)

  • Nobuya Inagaki

    (Kyoto University)

  • Andrew T. Hattersley

    (University of Exeter Medical School)

  • Tiinamaija Tuomi

    (Helsinki University Hospital
    University of Helsinki
    University of Helsinki
    University of Helsinki)

  • Miriam Cnop

    (Université Libre de Bruxelles
    Université Libre de Bruxelles)

  • Michael N. Weedon

    (University of Exeter Medical School)

Abstract

Finding new causes of monogenic diabetes helps understand glycaemic regulation in humans. To find novel genetic causes of maturity-onset diabetes of the young (MODY), we sequenced MODY cases with unknown aetiology and compared variant frequencies to large public databases. From 36 European patients, we identify two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants are enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio = 131, P = 1 × 10−4). We find similar results in non-Finnish European (n = 348, odds ratio = 43, P = 5 × 10−5) and Finnish (n = 80, odds ratio = 22, P = 1 × 10−6) replication cohorts. RFX6 heterozygotes have reduced penetrance of diabetes compared to common HNF1A and HNF4A-MODY mutations (27, 70 and 55% at 25 years of age, respectively). The hyperglycaemia results from beta-cell dysfunction and is associated with lower fasting and stimulated gastric inhibitory polypeptide (GIP) levels. Our study demonstrates that heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance.

Suggested Citation

  • Kashyap A. Patel & Jarno Kettunen & Markku Laakso & Alena Stančáková & Thomas W. Laver & Kevin Colclough & Matthew B. Johnson & Marc Abramowicz & Leif Groop & Päivi J. Miettinen & Maggie H. Shepherd &, 2017. "Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance," Nature Communications, Nature, vol. 8(1), pages 1-8, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00895-9
    DOI: 10.1038/s41467-017-00895-9
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