ABCC8-Related Congenital Hyperinsulinism via the ABCC8 Gene

Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous condition characterized by hypoglycemia (Glaser, B. et al. GeneReviews, 2003; Arnoux, J.B. et al. Early Hum Dev 86(5):287-294, 2010). The age of disease onset ranges from the neonatal period with severe forms to infancy or childhood with milder forms. Severe patients typically have extremely low serum glucose while milder cases present with variable hypoglycemia. Affected newborns also develop nonspecific symptoms including seizures, apnea, hypotonia, and poor feeding. Severity of disease manifestations can vary within the same family.

CHI is genetically caused by defects in genes involved in regulation of insulin secretion from pancreatic beta-cells (Kapoor, R. et al. Eur J Endocrinol 168(4):557-564, 2013; Snider, K. et al. J Clin Endocrinol Metab 98(2):E355-363, 2013). ABCC8-related congenital hyperinsulinism can be inherited in an autosomal recessive or dominant manner. ABCC8 has 39 coding exons that encode the sulfonylurea receptor 1 (SUR1) subunit of the ATP-sensitive potassium (KATP) channel in beta-cells. Genetic defects located throughout the ABCC8 gene are the most common identifiable cause of CHI with a wide mutation spectrum including missense, nonsense, regulatory, splicing site mutations, small deletion/insertions, large deletions/duplications, and complex rearrangements (Human Gene Mutation Database). While nearly all CHI patients with recessive ABCC8 mutations are medically unresponsive to the KATP channel agonist diazoxide, patients with dominant ABCC8 mutations can be responsive or nonresponsive to diazoxide (Kapoor, R. et al., 2013). Other genes have also been associated with CHI including KCNJ11 (the other KATP gene), GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A and UCP2 (Glaser, B. et al. GeneReviews, 2003; Kapoor, R. et al., 2013; Snider, K. et al., 2013; González-Barroso, M. et al. PLoS One. 3(12):e3850, 2008).

In a cohort of 417 CHI patients studied at the Hyperinsulinism Center in The Children's Hospital of Philadelphia (CHOP), approximately 75% (160/213) of mutations, regardless of inheritance pattern, were identified in the ABCC8 gene via DNA sequencing (Snider, K. et al. J Clin Endocrinol Metab. 98(2):E355-363, 2013).

This test provides full coverage of all coding exons of the ABCC8 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

It also includes targeted testing of a deep intronic splicing mutation c.1333-1013A>G, which was suggested as a founder mutation in the Irish population (Flanagan, S. et al. Am J Hum Genet 92(1):131-136, 2013).