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.Maturity-onset diabetes of the young (MODY) is the most common subtype of familial diabetes. Here, Patel et al. use targeted DNA sequencing of MODY patients and large-scale publically available data to show that RFX6 heterozygous protein truncating variants cause reduced penetrance MODY.
K.A.P. has a postdoctoral fellowship funded by the Wellcome Trust (110082/Z/15/Z). S.E.F. has a Sir Henry Dale Fellow-ship jointly funded by the Wellcome Trust and the Royal Society (105636/Z/14/Z). S.E. and A.T.H. are Wellcome Trust Senior Investigators (WT098395/Z/12/Z), and A.T.H. is also supported by a NIHR Senior Investigator award. M.N.W. is supported by the Wellcome Trust Institutional Strategic Support Fund (WT097835MF) and the Medical Research Council (MR/M005070/1). M.S. is supported by the NIHR Exeter Clinical Research Facility. Additional support came from the University of Exeter and the NIHR Exeter Clinical Research Facility. M.C. is supported by the European Union’s Horizon 2020 research and innovation programme, project T2DSystems, under grant agreement No 667191, and the Fonds National de la Recherche Scientifique (FNRS) and Actions de Recherche Concertées de la Communauté Française (ARC), Belgium. The FINNMODY and PPP-Botnia Studies have been financially supported by the Sigrid Juselius Foundation, the Folkhalsan Research Foundation, Helsinki University Central Hospital Research Foundation, Finnish Diabetes Research Foundation, Finnish Medical Society, Foundation for Pediatric Research, Ahokas Foundation, Ollqvist Foundation, Nordic Center of Excellence in Disease Genetics, EU-EXGENESIS), Signe and Ane Gyllenberg Foundation, Swedish Cultural Foundation in Finland, Finnish Diabetes Research Foundation, Foundation for Life and Health in Finland, Paavo Nurmi Foundation, Perklén Foundation, Närpes Health Care Foundation, and Diabetes Wellness Foundation. The study has also been supported by the Municipal Heath Care Center and Hospital in Jakobstad, Health Care Centers in Vasa, Närpes and Korsholm.
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Vol. 8, article 888
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