RT Journal Article SR Electronic T1 Heterozygous RFX6 protein truncating variants are associated with Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance JF bioRxiv FD Cold Spring Harbor Laboratory SP 101881 DO 10.1101/101881 A1 Kashyap A Patel A1 Jarno Kettunen A1 Markku Laakso A1 Alena Stančáková A1 Thomas W Laver A1 Kevin Colclough A1 Matthew B. Johnson A1 Marc Abramowicz A1 Leif Groop A1 Päivi J. Miettinen A1 Maggie H Shepherd A1 Sarah E Flanagan A1 Sian Ellard A1 Nobuya Inagaki A1 Andrew T Hattersley A1 Tiinamaija Tuomi A1 Miriam Cnop A1 Michael N Weedon YR 2017 UL http://biorxiv.org/content/early/2017/07/14/101881.abstract AB Finding new genetic causes of monogenic diabetes can help to understand development and function of the human pancreas. We aimed to find novel protein–truncating variants causing Maturity–Onset Diabetes of the Young (MODY), a subtype of monogenic diabetes. We used a combination of next–generation sequencing of MODY cases with unknown aetiology along with comparisons to the ExAC database to identify new MODY genes. In the discovery cohort of 36 European patients, we identified two probands with novel RFX6 heterozygous nonsense variants. RFX6 protein truncating variants were enriched in the MODY discovery cohort compared to the European control population within ExAC (odds ratio, OR=131, P=l×l0‐4). We found similar results in non–Finnish European (n=348, OR=43, P=5×l0‐5) and Finnish (n=80, OR=22, P=1×l0‐6) replication cohorts. The overall meta–analysis OR was 34 (P=l×l0‐16). RFX6 heterozygotes had reduced penetrance of diabetes compared to common HNF1A and HNF4A–MODY mutations (27%, 70% and 55% at 25 years of age, respectively). The hyperglycaemia resulted from beta–cell dysfunction and was 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.