GLUD1-Related Congenital Hyperinsulinism via the GLUD1 Gene

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 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.

GLUD1-caused congenital hyperinsulinism is also known as hyperinsulinism-hyperammonemia syndrome (HI/HA) (Stanley et al. 1998 and 2000). Children with this syndrome have symptomatic hypoglycemia and persistent elevations of plasma ammonium. Clinical manifestations included normal birth weight, late onset of hypoglycemia, diazoxide responsiveness, and protein-sensitive hypoglycemia. This disease can be sporadic or familial.

GLUD1-caused congenital hyperinsulinism (hyperinsulinism-hyperammonemia syndrome) is an autosomal dominant disorder caused by overactivity of glutamate dehydrogenase (GDH; encoded by GLUD1), which oxidizes glutamate to alpha-ketoglutarate (Stanley et al. 1998 and 2000). This enzyme is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver.

Documented genetic defects of GLUD1 (13 coding exons) to date are all missense mutations clustered in exons 6 through 12, which encode the catalytic and allosteric domains (Human Gene Mutation Database).

Other genes have also been associated with CHI including ABCC8, KCNJ11, GCK, HADH, SLC16A1, HNF4A, HNF1A and UCP2 (Glaser et al. 2003; Kapoor et al. 2013; Snider et al. 2013).

In a cohort of 48 unrelated HI/HA patients, a GLUD1 mutation was found in 25 probands (52%) (Stanley et al. 2000). In a cohort of 417 CHI patients studied at the Hyperinsulinism Center in The Children’s Hospital of Philadelphia (CHOP), among the diazoxide-responsive patients (n=118), GLUD1 mutations were found in 24 cases (20%) (Snider et al. 2013). In another cohort of 300 CHI patients studied in United Kingdom (Kapoor et al. 2013), among the diazoxide-responsive patients (n=183), GLUD1 mutations were found in 16 cases (8.7%).

This test provides full coverage of all coding exons of the GLUD1 gene 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 full 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).