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Background  Maturity-onset of the young (MODY) is a clinically heterogeneous form of diabetes characterized by an autosomal-dominant mode of inheritance, an onset before the age of 25 years, and a primary defect in the pancreatic beta-cell function. Approximately 30% of MODY families remain genetically unexplained (MODY-X). Here, we aimed to use whole-exome sequencing (WES) in a four-generation MODY-X family to identify a new susceptibility gene for MODY.    Methodology  WES (Agilent-SureSelect capture/Illumina-GAIIx sequencing) was performed in three affected and one non-affected relatives in the MODY-X family. We then performed a high-throughput multiplex genotyping (Illumina-GoldenGate assay) of the putative causal mutations in the whole family and in 406 controls. A linkage analysis was also carried out.    Principal Findings  By focusing on variants of interest ( i.e.  gains of stop codon, frameshift, non-synonymous and splice-site variants not reported in dbSNP130) present in the three affected relatives and not present in the control, we found 69 mutations. However, as WES was not uniform between samples, a total of 324 mutations had to be assessed in the whole family and in controls. Only one mutation (p.Glu227Lys in  KCNJ11 ) co-segregated with diabetes in the family (with a LOD-score of 3.68). No  KCNJ11  mutation was found in 25 other MODY-X unrelated subjects.    Conclusions/Significance  Beyond neonatal diabetes mellitus (NDM),  KCNJ11  is also a MODY gene (‘MODY13’), confirming the wide spectrum of diabetes related phenotypes due to mutations in NDM genes ( i.e. KCNJ11 ,  ABCC8  and  INS ). Therefore, the molecular diagnosis of MODY should include  KCNJ11  as affected carriers can be ideally treated with oral sulfonylureas.

Whole-Exome Sequencing and High Throughput Genotyping Identified KCNJ11 as the Thirteenth MODY Gene