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, Päivi J. Miettinen, Maggie H. Shepherd, Sarah E. Flanagan, Sian Ellard, Nobuya Inagaki, Andrew T. Hattersley, Tiinamaija Tuomi, Miriam Cnop () and Michael N. Weedon ()
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Kashyap A. Patel: University of Exeter Medical School
Jarno Kettunen: Helsinki University Hospital
Markku Laakso: Kuopio University Hospital
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
Päivi J. Miettinen: University of Helsinki and Helsinki University Hospital
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
Miriam Cnop: Université Libre de Bruxelles
Michael N. Weedon: University of Exeter Medical School

Nature Communications, 2017, vol. 8, issue 1, 1-8

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00895-9

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