A novel INS mutation in a family with MODY: variable insulin secretion and putative mechanisms.

Insulin gene (INS) mutations are a rare form of maturity-onset diabetes of the young (MODY), a heterogeneous group of autosomal dominant diabetes with at least fourteen confirmed causative genes. Here we describe a family with MODY from a novel INS mutation detected using massively parallel sequencing (MPS).The proband presented aged 11 years with mild diabetic ketoacidosis. She was negative for IA2 and GAD antibodies. She had a strong family history of diabetes, including both siblings and her mother, none of whom had ketosis but who were considered to have type 1 diabetes and managed on insulin; and her maternal grandfather, who was managed for decades on sulfonylureas. Of note, her younger sister had insulin deficiency but an elevated fasting proinsulin:insulin ratio of 76% (ref 5-30%). Sanger sequencing of HNF4A, HNF1A and HNF1B in the proband was negative.The proband underwent targeted MPS using custom-designed amplicon panel and sequenced on an Illumina MiSeq.A heterozygous INS mutation c.277G>A (p.Glu93Lys) was detected. Sanger sequencing confirmed the variant segregated with diabetes within the family. Structural analysis of this variant suggested a disruption of a critical hydrogen bond between insulin and the insulin receptor; however the clinical picture in some individuals also suggested abnormal insulin processing and insulin deficiency.This family has a novel INS mutation and demonstrated variable insulin deficiency. MPS represents an efficient method of MODY diagnosis in families with rarer gene mutations.