Congenital Hyperinsulinism Panel

Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous condition characterized by hypoglycemia (Glaser et al. 2003; Arnoux et al. 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 et al. 2013; Snider et al. 2013). CHI can be inherited in an autosomal dominant or recessive manner. Proteins encoded by CHI-associated genes include the ATP-sensitive potassium (KATP) channels (ABCC8 and KCNJ11), the glutamate dehydrogenase (GLUD1), nuclear transcription factors controlling pancreatic development (HNF1A and HNF4A), the glucokinase (a glucose sensor in pancreatic beta-cells) (GCK), a member of the 3-hydroxyacyl-CoA dehydrogenase family (HADH), a mitochondrial anion carrier protein (UCP2) and a plasma membrane pyruvate transporter (SLC16A1) (Glaser et al. 2003; Kapoor et al. 2013; Snider et al. 2013). Our current CHI NGS panel covers all 9 genes.

Defects in KATP channels (ABCC8 and KCNJ11) are the most common cause of CHI. KATP-associated CHI 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) channels in beta-cells. Genetic defects located throughout the ABCC8 gene have a wide mutation spectrum including missense, nonsense, regulatory, splicing site mutations, small deletion/insertions, large deletions/duplications, and complex rearrangements (Human Gene Mutation Database).

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).

GLUD1-caused congenital hyperinsulinism (hyperinsulinism-hyperammonemia syndrome) is the second most common type of CHI caused by dominant activating mutations in the GLUD1 gene (13 coding exons), which encodes glutamate dehydrogenase (GDH). This enzyme is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver.

The third most common causes of CHI are dominant activating mutations in the GCK gene (10 coding exons), which encodes glucokinase. Dominant inactivating GCK mutations cause MODY type 2 (MODY2) (McDonald et al. 2013). More information about GCK can be found in the Test #1220 Description (Sanger sequencing).

The HADH gene (9 coding exons) encodes short-chain L-3-hydroxyacyl-CoA dehydrogenase, a fatty acid oxidation enzyme in the mitochondrial matrix. Recessive inactivating HADH mutations can cause CHI (Clayton et al. 2001).

The UCP2 gene (6 coding exons) encodes a mitochondrial uncoupling protein involved in nonshivering thermogenesis, obesity and diabetes. Dominant inactivating UCP2 mutations can cause CHI (Gonzalez-Barroso et al. 2008).

The genes HNF1A (also known as TCF1; 10 coding exons) and HNF4A (10 coding exons) encode hepatocyte nuclear factor 1-alpha and 4-alpha, respectively. These hepatic nuclear factor transcription factors regulate the expression of insulin as well as alter beta-cell development, proliferation and cell death in the mature beta-cells. Defects in HNF1A and HNF4A are the major cause of maturity onset diabetes of the young (MODY) (McDonald et al. 2013). In addition, dominant mutations in both HNF1A and HNF4A can cause CHI early in life and diabetes later (Stanescu et al. 2012).

The SLC16A1 gene (4 coding exons) encodes a plasma membrane monocarboxylate transporter 1 (MCT1). Dominant activating SLC16A1 mutations cause exercise-induced CHI secondary to failed silencing of monocarboxylate transporter 1 in pancreatic beta cells (Otonkoski et al. 2007).

In a cohort of 417 CHI patients studied at the Hyperinsulinism Center in The Children’s Hospital of Philadelphia (CHOP) (Snider et al. 2013), all nine genes were tested. Mutations were identified in 91% (272 of 298) of diazoxide-unresponsive probands (ABCC8, KCNJ11, and GCK), and in 47% (56 of 118) of diazoxide-responsive probands (ABCC8, KCNJ11, GLUD1, HADH, UCP2, HNF4A, and HNF1A). In another cohort of 300 CHI patients studied in United Kingdom (Kapoor et al. 2013), mutations were identified in 45.3% of patients (136/300) in eight tested genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A and HNF1A). KATP (ABCC8 and KCNJ11) mutations were the most common genetic cause identified (109/300, 36.3%). Mutations in ABCC8/KCNJ11 were identified in 92 (87.6%) diazoxide-unresponsive patients (n=105). Among the diazoxide-responsive patients (n=183), mutations were identified in 41 patients (22.4%), including mutations in ABCC8/KCNJ11 (15), HNF4A (7), GLUD1 (16) and HADH (3).

Clinical sensitivity for gross deletions and duplications in the HADH gene cannot be predicted as few patients have been reported. One gross deletion has been reported (Human Gene Mutation Database).

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).