Whole exome sequencing reveals novel candidate gene variants for MODY.

Maturity-onset diabetes of the young (MODY) is a monogenic subtype of diabetes mellitus. Although 14 genes were associated to different subtypes of MODY, 30-40% of MODY patients have unidentified genetic mutations. In this study, we conducted whole exome sequencing (WES) in four Turkish MODY suspected patients in two families who do not carry any pathological variants in four frequent MODY genes (HNF1A, GCK, HNF1B and HNF4A). Initially, the variants were scanned for the known 14 MODY genes and a gene set related to glucose metabolism. Secondly, the destructive (frameshift, inframe insertion/deletion, initiator codon variant, splice acceptor/ donor variant, stop gained/lost) and missense variants in novel candidate genes shared by two patients of the same family were assessed by different bioinformatic tools. As a result, a total of three rare and novel probably pathogenic heterozygous missense variants (p.His307Gln in c-Myc, p.Asp129Asn in CDK4 and p.Gly107Ser in ARHGDIA) in candidate genes were identified in two families. This study revealed the presence of nonsynonymous alterations in novel candidate genes which were implicated in the insulin secretion. This is the first WES study which reveals novel candidate genes in Turkish MODY patients although functional analyses are required to confirm the pathogenicity of these variants.