Insulin gene mutations linked to permanent neonatal diabetes mellitus in Indian population

Neonatal diabetes mellitus (NDM) is a rare monogenic disorder of pancreatic beta cell mass and/or function. In the present study we aimed to evaluate the INS gene mutations in a cohort of children with Permanent Neonatal Diabetes Mellitus (PNDM) and to explore the clinical and genetic characteristics of PNDM caused by INS mutations. Direct sequencing of all exons of INS genes was carried out in 189 children with PNDM. Clinical and biochemical data were collected and correlated. The pathogenicity of mutations was determined based on the American College of Medical Genetics and Genomics and Association of Medical Pathology guidelines. Two novel mutations (His34Pro, Leu35Met) in a compound heterozygous state and seven known mutations (Gly32Ser, Phe48Cys, Arg89Cys, Cys96Tyr, Ser98Ile, Try108Asp and Cys109Phe) in the INS gene were identified in 8 patients out of the total of 189 PNDM children studied. Four mutations were involved in defects with disulphide bond formation and hence were in crucial regions of the gene. All the mutations were de novo in origin. This is the first comprehensive study from India to investigate the insulin gene mutations in PNDM and to show that INS gene mutations also contribute to the causation of PNDM. •This is the first study describing the spectrum of INS gene mutations in Indian PNDM patients.•Four mutations that created unpaired cysteine and five mutations that involved non-cysteine residues were identified.•Five mutations that involved non cysteine residues were G32S, H34P, L35M, S98I and Y108D•Bioinformatics analysis and ACMG guidelines predicted that these variations could be damaging or disease causing.•NDM children in this study are on insulin therapy, were born to non- consanguineous parents and carried de novo mutations.