TY - JOUR T1 - Heterozygous <em>RFX6</em> protein truncating variants cause Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance JF - bioRxiv DO - 10.1101/101881 SP - 101881 AU - Kashyap A Patel AU - Markku Laakso AU - Alena Stančáková AU - Thomas W Laver AU - Kevin Colclough AU - Matthew B Johnson AU - Jarno Kettunen AU - Tiinamaija Tuomi AU - Miriam Cnop AU - Maggie H. Shepherd AU - Sarah E Flanagan AU - Sian Ellard AU - Andrew T Hattersley AU - Michael N Weedon Y1 - 2017/01/01 UR - http://biorxiv.org/content/early/2017/01/22/101881.abstract N2 - 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=130, P=6×10-28). We found similar results in non-Finnish European (n=348, OR=26, P=6×10-14) and Finnish (n=80, OR=22, P=5×10-18) replication cohorts. 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). Our study demonstrates that heterozygous RFX6 protein truncating variants are a new cause of MODY with reduced penetrance. ER -