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Congenital hyperinsulinism of infancy (CHI) is a rare disorder characterized by severe hypoglycemia due to inappropriate insulin secretion. The genetic causes of CHI have been found in genes regulating insulin secretion from pancreatic β-cells; recessive inactivating mutations in the  ABCC8  and  KCNJ11  genes represent the most common events. Despite the advances in understanding the molecular pathogenesis of CHI, specific genetic determinants in about 50 % of the CHI patients remain unknown, suggesting additional locus heterogeneity. In order to search for novel loci contributing to the pathogenesis of CHI, we combined a family-based association study, using the transmission disequilibrium test on 17 CHI patients lacking mutations in  ABCC8 / KCNJ11,  with a whole-exome sequencing analysis performed on 10 probands. This strategy allowed the identification of the potential causative mutations in genes implicated in the regulation of insulin secretion such as transmembrane proteins ( CACNA1A, KCNH6, KCNJ10, NOTCH2, RYR3, SCN8A, TRPV3, TRPC5 ), cytosolic ( ACACB, CAMK2D, CDKAL1, GNAS, NOS2, PDE4C, PIK3R3 ) and mitochondrial enzymes ( PC, SLC24A6 ), and in four genes ( CSMD1 ,  SLC37A3 ,  SULF1 ,  TLL1 ) suggested by TDT family-based association study. Moreover, the exome-sequencing approach resulted to be an efficient diagnostic tool for CHI, allowing the identification of mutations in three causative CHI genes ( ABCC8 ,  GLUD1, and HNF1A)  in four out of 10 patients. Overall, the present study should be considered as a starting point to design further investigations: our results might indeed contribute to meta-analysis studies, aimed at the identification/confirmation of novel causative or modifier genes.

Whole Genome SNP Genotyping and Exome Sequencing Reveal Novel Genetic Variants and Putative Causative Genes in Congenital Hyperinsulinism