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

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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.


  • Kashyap A. Patel
  • Jarno Kettunen
  • Markku Laakso
  • Alena Stančáková
  • Thomas W. Laver
  • Kevin Colclough
  • Matthew B. Johnson
  • Marc Abramowicz
  • Leif Groop
  • Païvi J. Miettinen
  • Maggie H. Shepherd
  • Sarah E Flanagan
  • Sian Ellard
  • Nobuya Inagaki
  • Andrew T. Hattersley
  • Tiinamaija Tuomi
  • Miriam Cnop
  • Michael N. Weedon
External organisations
  • University of Exeter
  • University of Eastern Finland
  • Free University of Brussels (ULB)
  • Institute for Molecular Medicine Finland (FIMM)
  • Kyoto University
  • Helsinki University Central Hospital
  • Kuopio University Hospital
  • Royal Devon & Exeter Hospital
  • Skåne University Hospital
  • University of Helsinki
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Endocrinology and Diabetes
Original languageEnglish
Article number888
JournalNature Communications
Issue number1
Publication statusPublished - 2017 Dec 1
Publication categoryResearch