Identification of novel variants in neonatal diabetes mellitus genes in Egyptian patients with permanent NDM

Neonatal diabetes mellitus (NDM) is a monogenic form of diabetes resulting from mutations in more than 20 different genes encoding proteins playing a key role in the normal function of the pancreatic beta-cell. Mutations in the genes encoding the ATP-sensitive potassium channel, ABCC8, and KCNJ11 and insulin (INS) gene are the most common causes of NDM; however, in consanguineous populations, EIF2AK3 mutations are more common. Identification of the causative mutations by genetic testing is critical for appropriate management and to guide genetic counseling. To determine the genetic etiology of NDM in diabetic neonates and infants diagnosed before the age of 1 year and to describe their phenotype/genotype characteristics, DNA sequencing of coding regions and intronic boundaries of ABCC8, KCNJ11, INS, and EIF2AK3 genes was undertaken in 20 patients. Further, targeted next-generation sequencing was performed for other genes known to cause NDM. ABCC8 mutations were found in two patients (10%), with compound heterozygous mutations (p.N131 K/p.R598*) in one patient and a homozygous mutation (p.R1554Q) in the another patient. Heterozygous p.A174G and p.V59M mutations of KCNJ11 were identified in two patients (10%), and homozygous EIF2AK3 mutations were identified in two further patients (p.T905fs and p.R653T) (10%). No INS mutations were identified. Further testing identified a SLC19A2 mutation (p.W387*) in one patient (5%) and the same homozygous GCK mutation in two siblings (p.A188T). ABCC8, KCNJ11, and EIF2AK3 mutations were the main genetic causes of permanent NDM among Egyptian neonates.