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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.

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