Recent years have seen significant progress towards defining the genetic aetiology of neonatal diabetes with >20 subtypes identified. It is likely that all cases of neonatal diabetes result from a single gene disorder since markers of autoimmunity associated with type 1 diabetes are rare in patients diagnosed before 6 months.
Heterozygous activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the KATP channel are the most common cause of neonatal diabetes. Most of these patients can achieve improved glycaemic control on sulphonylurea tablets. Around 20% also have developmental delay which may be improved through high dose sulphonylurea therapy. Mutations in the INS gene are reported as the second most common cause. Most are dominant missense mutations that cause misfolding of the insulin molecule leading to β cell apoptosis but recessive loss-of-function mutations preventing insulin synthesis are more common in consanguineous families. Transcription factor mutations identified through candidate gene studies or homozygosity mapping strategies account for the majority of other known cases.
The advent of next generation studies allows a hypothesis free approach for finding new genetic aetiologies. Exome sequencing has shown that de novo GATA6 mutations are the most common cause of pancreatic agenesis. A genetic approach to gene discovery was necessary since mouse models failed to recapitulate the phenotype. The human phenotype associated with heterozygous GATA6 mutations is very variable, ranging from complete absence of the pancreas, gall bladder and cardiac malformations, to patients with isolated diabetes diagnosed in adulthood. Most recently, a combination of genetic linkage, genome sequencing and epigenomic annotation revealed a novel enhancer 25 kb downstream from PTF1A in which mutations cause pancreatic agenesis with no cerebellar phenotype in contrast to the PTF1A coding mutations that result in cerebellar agenesis.
20 - 22 Sep 2014
European Society for Paediatric Endocrinology