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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.

Original publication




Journal article


Pediatric diabetes

Publication Date



Department of Endocrinology, Lady Cilento Children's Hospital 501 Stanley Street, South Brisbane, QLD, Australia.