Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood

Abstract

Objective: Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood.

Research design and methods: The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes.

Results: We identified heterozygous INS mutations in 33 of 141 probands diagnosed at <6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K(+) channel mutation carriers (11 vs. 8 weeks, P < 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant.

Conclusions: We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.

FIG. 1. Mutations identified in the preproinsulin molecule.

Black circles represent amino acid changes identified in probands with diabetes diagnosed before 12 months, grey circles represent amino acid changes identified in probands with possible MODY. Where the number of probands with the mutation is greater than one, the total number is indicated in the square brackets.

FIG. 2. Partial pedigrees for families with multiple individuals affected with diabetes.

Filled symbols represent patients with diabetes. The genotype is shown underneath each symbol, N/N denotes no mutation identified. Below the genotype is the age of diagnosis of diabetes. An arrow indicates the proband.

FIG. 3. Penetrance of INS gene mutations in 46 individuals from 35 families where the proband was diagnosed in the first year of life.

The percentage of patients with an INS mutation and diabetes at any given age is shown.

FIG. 4. Etiology of permanent neonatal diabetes in a cohort of 279 patients diagnosed before 6 months.

The number of probands with mutations identified is shown, together with the percentages for each etiology. All subjects of unknown etiology were sequenced for KCNJ11, ABCC8 and INS.

FIG. 5. Partial pedigrees for novel INS mutations identified in probands with MODY and young T2D.

Filled symbols represent patients with diabetes. The genotype is shown underneath each symbol, N/N denotes no mutation identified. Below the genotype is the age at diagnosis of diabetes and current treatment. An arrow indicates the proband.