Metabolic Hypoglycemia Panel

Recurrent episodes of abnormally low blood glucose levels, termed hypoglycemia, can occur in infants, children and adults (Marles and Casiro. 1998. PubMed ID: 20401190; Cryer et al. 2009. PubMed ID: 19088155; Douillard et al. 2012. PubMed ID: 22587661; Saudubray and Charpentier 2014; Thornton et al. 2015. PubMed ID: 25957977; Ghosh et al. 2016. PubMed ID: 26718813). Hypoglycemia may occur at different times, such as after eating (postprandial), during fasting, or after exercise, depending on the cause. Early in a hypoglycemic episode, an individual may display symptoms such as pallor, anxiety, sweating, weakness, tremors, nausea and vomiting, and if untreated, these symptoms may progress to irritability, confusion, slurred speech, headache, seizures and coma. As glucose is the primary fuel for the brain, these episodes can cause permanent brain injury if not treated urgently. Brain injury from untreated hypoglycemic episodes can lead to clinical symptoms such as neurocognitive defects, memory deficits, aphasia and hemiparesis (Ghosh et al. 2016. PubMed ID: 26718813).

Hypoglycemic episodes are often brought on by illness or other metabolic stress, and can be caused by many different factors. The two most common are diabetes mellitus and idiopathic ketotic hypoglycemia (IKH). IKH is a diagnosis of exclusion. Before concluding an individual has IKH, other less common causes of hypoglycemia should be ruled out. Other potential causes include endocrine disorders, inborn errors of metabolism (IEMs), and liver disease. The IEMs known to be associated with hypoglycemia include several of the glycogen storage diseases (GSDs), disorders of carbohydrate metabolism, branched chain organic acidemias, and disorders of fatty acid oxidation (FAOs). This sequencing panel is focused primarily on the GSDs, disorders of carbohydrate metabolism, FAOs that are associated with hypoglycemic episodes, although genes that lead to a few other disorders with similar clinical features are also included (Marles and Casiro. 1998. PubMed ID: 20401190; Cryer et al. 2009. PubMed ID: 19088155; Douillard et al. 2012. PubMed ID: 22587661; Saudubray and Charpentier 2014; Thornton et al. 2015. PubMed ID: 25957977; Ghosh et al. 2016. PubMed ID: 26718813). Some of the genes in this panel are known to be associated with disorders that result in ketotic hypoglycemia, others with non-ketotic hypoglycemia.

Branched chain organic acidemias and FAOs often have other distinctive biochemical and/or clinical features, and thus they not all included in this panel. However, all the relevant genes are available for sequencing at PreventionGenetics. In addition, for patients with suspected congenital hyperinsulinism, a specific NextGen sequencing test is available.

Nearly all of the disorders associated with genes in this panel exhibit autosomal recessive inheritance. The only exceptions are the X-linked disorders glycerol kinase deficiency (caused by variants in the GK gene), glycogen storage disease type IXa (caused by variants in the PHKA2 gene), and the autosomal dominant disorders familial hyperinsulinemic hypoglycemia 7 and monocarboxylate transporter 1 deficiency (both caused by variants in the SLC16A1 gene).

The AGL, G6PC1/G6PC, GYS2, PGM1, PHKA2, PHKB, PHKG2, PRKAG2, PYGL, SLC2A2 and SLC37A4 genes encode proteins involved in the metabolism of glycogen. The ALDOB, FBP1, GALT, GK, PC, PCK1, PCK2 and SLC16A1 genes encode proteins that are involved in carbohydrate metabolism or transport. The ACADM, ACADVL, ETFA, ETFB, ETFDH, HADH, MLYCD, SLC22A5, and SLC25A20 genes encode proteins that are involved in fatty acid metabolism. The ACAT1, HMGCL, HMGCS2, and OXCT1 genes encode proteins involved in amino acid and/or ketone metabolism. ACSF3 encodes an acyl-CoA synthetase protein of uncertain function. The CA5A gene encodes an intramitochondrial carbonic anhydrase that provides bicarbonate for multiple mitochondrial enzymes. The DGUOK and MPV17 genes encode proteins that are involved in maintenance of mitochondrial DNA. The NNT gene encodes a pyridine nucleotide transhydrogenase, which is an inner mitochondrial membrane protein that is part of the energy-transfer system of the respiratory chain. The TANGO2 gene encodes a transport and golgi organization protein, although its function is not currently well understood.

See individual gene test descriptions for additional information on molecular biology of gene products and spectra of pathogenic variants.

The clinical sensitivity of this specific grouping of genes is difficult to estimate as we are unaware of any reports in the literature in which these genes have been sequenced together in a patient cohort with hypoglycemia as the primary indication for testing. The clinical sensitivity of sequencing the individual genes is high in patient groups with biochemical and/or enzymatic diagnoses of the relevant disorders; details are available on the individual test description pages. Analytical sensitivity is expected to be high as most variants reported in these genes are detectable via direct sequencing.

Overall, large (exonic level, usually multi-exon) deletions and duplications are rare in the genes in this panel. Large deletions and/or duplications have been documented in Human Gene Mutation Database (HGMD) for over half of the genes in this panel. However, such copy number variants only appear to be a somewhat common cause of disease in five of the genes in this panel (ALDOB, FBP1, GALT, PHKA2 and TANGO2; see below for additional details).

Gross deletions in the ALDOB gene have been reported to account for up to 20% of pathogenic ALDOB alleles (Esposito et al. 2010. PubMed ID: 20848650; Ferri et al. 2012. PubMed ID: 23430936; Baker et al. 1993. PubMed ID: 26677512).

At least 6 gross deletions have been reported in the FBP1 gene (HGMD). Deletion of one or more exons on 8 out of 26 alleles has been reported, suggesting a clinical sensitivity of ~30% for deletion and duplication testing of the FBP1 gene (Santer et al. 2016. PubMed ID: 27101822).

While the great majority of GALT variants are expected to be detected via gene sequencing, several exonic or whole-gene deletions have been reported (HGMD). In general, these deletions have been observed in a single patient, although a ~5.5 kb complex deletion is common in those of Ashkenazi Jewish descent (Barbouth et al. 2006. PubMed ID: 16540753; Coffee et al. 2006. PubMed ID: 17079880; Berry 2017. PubMed ID: 20301691). If desired, the specific Ashkenazi Jewish ~5.5 kb deletion can be tested by our PCR-based deletion test.

Seven gross deletions have been reported in the PHKA2 gene (HGMD). It is difficult to estimate the fraction of GSD IXa patients harboring a gross deletion as this value has varied in different studies (for example, 2 out of 26 patients reported in Davit-Spraul et al. 2011. PubMed ID: 21646031, and 3 out of 6 patients reported in Choi et al. 2016. PubMed ID: 27103379). It is, however, apparent that large copy number variants in PHKA2 are a relatively common cause of disease in GSD IXa patients.

Gross deletions have been reported to account for up to ~50% of pathogenic TANGO2 alleles, with deletions of exons 3-9 or 4-6 being the most commonly reported (Kremer et al. 2016. PubMed ID: 26805782; Lalani et al. 2016. PubMed ID: 26805781; Lalani et al. 2018. PubMed ID: 29369572).

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

This panel typically provides 99.7% 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).