Hypoglycemia Panel - Expanded

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). We offer smaller panels focused solely on the IEMs more commonly associated with hypoglycemia, as well as a smaller panel focused specifically on congenital hyperinsulinism. This particular Expanded Hypoglycemia panel includes all of the genes on the Metabolic Hypoglycemia and Congenital Hyperinsulinism panels as well as some other disorders less commonly associated with hypoglycemia (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; Gillis and Gillis. 2019. PubMed ID: 20301549). Some of the genes in this panel are known to be associated with disorders that result in ketotic hypoglycemia, others with non-ketotic hypoglycemia.

Molecular testing is useful to confirm a clinical diagnosis of a genetic cause of the observed hypoglycemic episodes, or rule out such causes in cases of idiopathic ketotic hypoglycemia (IKH). Molecular diagnosis for a patient with recurrent hypoglycemic episodes may help with determining appropriate treatment measures, assessment of recurrence risks, and allow for appropriate screening for potential future symptoms. 

The majority of the disorders associated with genes in this panel exhibit autosomal recessive inheritance, with the following exceptions:

Autosomal dominant inheritance: AKT2, APPL1, ASXL2, BLK, CACNA1C, GLUD1, HNF1A, HNF1B, HNF4A, KLF11, KMT2D, LHX4, MAFA, MTOR, NSD1  PAX4, RNF125, and UCP2.

Autosomal dominant and/or recessive inheritance: ABCC8, CPT2, GCK, INS, INSR, KCNJ11, PDX1 and SLC16A1. 

X-linked inheritance: GK, HSD17B10, PHKA2, KDM6A and TAFAZZIN. 

The genes included in this test are associated with disorders that can be broadly classified into several categories based on the pathway(s) within the cell that are disrupted:

Disorders of Amino Acid or Ketone Metabolism: ACAT1, ADK, ALDH7A1, AUH, BCKDHA, BCKDHB, DBT, FAH, GCDH, GLUD1, HMGCL, HMGCS2,  HSD17B10,  IVD,  MCCC1,  MCCC2,  MMUT,  OXCT1, PCCA, PCCB

Congenital Disorders of Glycosylation: ALG12, MPI

Developmental or Cellular Regulation: ASXL2, CACNA1C, LHX4, MTOR, PPP1R15B, PTF1A, RNF125

Disorders of Carbohydrate Metabolism, Transport, and Absorption: AGL, ALDOB, FBP1, G6PC1/G6PC, GALT, GCK, GK, GYS2, PC, PCK1, PCK2, PGM1, PHKA2, PHKB, PHKG2, PRKAG2, PYGL, SLC2A2, SLC37A4

Disorders of Fatty Acid Oxidation and Transport: ACAD9, ACADM, ACADS, ACADSB, ACADVL, ACSF3, CPT1A, CPT2, ETFA, ETFB, ETFDH, HADH, HADHA, HADHB, MLYCD, SLC22A5, SLC25A20, TANGO2

Disorders of Insulin Secretion and Signaling: ABCC8, AKT2, APPL1, BLK, HNF1A, HNF1B, HNF4A, INS, INSR, KCNJ11, KLF11, MAFA, NEUROD1, PAX4, PDX1, UCP2

Disorders of Nuclear Encoded Mitochondrial Genes: ATP5F1D, CA5A, DGUOK, GATB, LRPPRC, MICOS13, MPV17, MRPS23, MRPS28, MRPS7, MTO1, SERAC1, TAFAZZIN, TFAM, UQCC3, UQCRB, UQCRC2

Other Metabolic Processes: CYP7B1, DBH, MPC1, MRAP, NNT, NR1H4, OGDH, PNPO, SLC16A1, SLC25A13, TALDO1

For the majority of genes on this panel, large copy number variants (gross deletions or duplications/insertions) are a rare cause of disease. Exceptions to this may include ALDH7A1, ALDOB, FBP1, GALT, HNF1B, INSR, PCCA, PHKA2, and TANGO2. It should also be noted that, to our knowledge, de novo variants are not commonly reported for the majority of genes in this panel, although they have been reported in ABCC8, AKT2, ASXL2, CACNA1C, GCK, GLUD1, HNF1A, HNF1B, HNF4A, INS, INSR, KCNJ11, LHX4, MTOR, RNF125, and TAFAZZIN.

See individual gene summaries for more information about 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.

With regards to patients with congenital hyperinsulinism (CHI), some data are available. In a cohort of 417 CHI patients studied at the Hyperinsulinism Center in The Children’s Hospital of Philadelphia (CHOP) (Snider et al. 2013. PubMed ID: 23275527), nine genes were tested. Pathogenic variants 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. PubMed ID: 23345197), pathogenic variants were identified in 45.3% of patients (136/300) in eight tested genes (ABCC8, KCNJ11, GLUD1, GCK, HADH, SLC16A1, HNF4A, HNF1A). KATP (ABCC8 and KCNJ11) pathogenic variants were the most common genetic cause identified (109/300, 36.3%). Pathogenic variants in ABCC8/KCNJ11 were identified in 92 (87.6%) diazoxide-unresponsive patients (n=105). Among the diazoxide-responsive patients (n=183), pathogenic variants were identified in 41 patients (22.4%), including pathogenic variants in ABCC8/KCNJ11 (15), HNF4A (7), GLUD1 (16) and HADH (3).

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

This panel typically provides 99.8% 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).