KCNJ11-Related Congenital Hyperinsulinism via the KCNJ11 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):E355-563, 2013). KCNJ11-related congenital hyperinsulinism can be inherited in an autosomal recessive or dominant manner. KCNJ11 is a single exon gene that encodes the Kir6.2 subunit of the ATP-sensitive potassium (KATP) channels in beta-cells. Genetic defects located throughout the KCNJ11 gene include missense, nonsense, regulatory, and small deletion/insertions (Human Gene Mutation Database). While CHI patients with recessive KCNJ11 mutations are medically unresponsive to the KATP channel agonist diazoxide, dominant KCNJ11 mutations are exclusively associated with diazoxide-responsive patients (Kapoor, R. et al., 2013; Snider, K. et al., 2013).

Other genes have also been associated with CHI including ABCC8 (the other KATP gene), GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A and UCP2 (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 11% (23/213) of mutations, regardless of inheritance pattern, were identified in the KCNJ11 gene via DNA sequencing (Snider, K. et al. J Clin Endocrinol Metab 98(2):E355-563, 2013). In another cohort of 300 CHI patients studied in the United Kingdom (Kapoor, R. et al. Eur J Endocrinol 168(4):557-564, 2013), KCNJ11 mutations identified via DNA sequencing were found in 10 out of 105 (9.5%) diazoxide-nonresponsive CHI patients including 6 patients with homozygous mutations and 4 patients affected by focal disease with a paternally inherited mutation. Only one of 183 diazoxide-responsive CHI patients had a heterozygous dominant KCNJ11 mutation.

This test provides full coverage of the single exon of the KCNJ11 gene plus ~10 bases of flanking noncoding DNA and ~120 bp upstream of the start codon. We define full coverage as >20X NGS reads or Sanger sequencing.