Permanent diabetes during the first year of life: multiple gene screening in 54 patients

Aims/hypothesis. Investigate the genetic etiology of permanent diabetes mellitus with onset in the first 12 months of age. Methods. We studied forty-six probands with permanent, insulin-requiring diabetes with onset within the first 6 months of life (Permanent Neonatal Diabetes Mellitus/PNDM-Monogenic diabetes of infancy/MDI) (Group 1) and 8 subjects with diabetes diagnosed between 7 to 12 months of age (Group 2). KCNJ11, INS, and ABCC8 genes were sequentially sequenced in all patients. For those who were negative in the initial screening, we examined ERN1, CHGA, CHGB, NKX6-1 genes and -in selected probands- CACNA1C, GCK, FOXP3, NEUROG3 and CDK4. The incidence rate for PNDM/MDI was calculated using the database of Italian patients collected from 1995-2009. Results. In Group 1 we found mutations in KCNJ11, INS, and ABCC8 genes in 23 (50%), 9 (19.5%) and 4 (8.6%) patients respectively, and a single homozygous mutation in GCK (2.1%). In Group 2, we identified a KCNJ11 mutation. No genetic defects were detected in other loci. The incidence rate of PNDM/MDI in Italy is estimated to be 1:210,287. Conclusions/interpretation. Genetic mutations were identified in ~75% of non-consanguineous probands with PNDM/MDI by sequential screening of KCNJ11, INS and ABCC8 genes within the first 6 months of age. This percentage decreases to 12% in those with diabetes diagnosed between 7 to 12 months. Patients belonging to the latter group may either carry mutations in genes different from those commonly found in PNDM/MDI or have developed an early-onset form of autoimmune diabetes