Metabolic Hypoglycemia Panel

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy Genes Gene CPT Codes Copy CPT Codes
10365 ACADM 81479,81479 Order Options and Pricing
ACADVL 81406,81479
ACAT1 81479,81479
ACSF3 81479,81479
AGL 81407,81479
ALDOB 81479,81479
CA5A 81479,81479
DGUOK 81405,81479
ETFA 81479,81479
ETFB 81479,81479
ETFDH 81479,81479
FBP1 81479,81479
G6PC1 81479,81479
GALT 81406,81479
GK 81479,81479
GYS2 81479,81479
HADH 81479,81479
HMGCL 81479,81479
HMGCS2 81479,81479
MLYCD 81479,81479
MPV17 81405,81404
NNT 81479,81479
OXCT1 81479,81479
PC 81406,81479
PCK1 81479,81479
PCK2 81479,81479
PGM1 81479,81479
PHKA2 81479,81479
PHKB 81479,81479
PHKG2 81479,81479
PRKAG2 81406,81479
PYGL 81479,81479
SLC16A1 81479,81479
SLC22A5 81405,81479
SLC25A20 81405,81404
SLC2A2 81479,81479
SLC37A4 81406,81479
TANGO2 81479,81479
Test Code Test Copy Genes Panel CPT Code Gene CPT Codes Copy CPT Code Base Price
10365Genes x (38)81479 81404, 81405, 81406, 81407, 81479 $960 Order Options and Pricing

Pricing Comments

We are happy to accommodate requests for testing single genes in this panel or a subset of these genes. The price will remain the list price. If desired, free reflex testing to remaining genes on panel is available. Alternatively, a single gene or subset of genes can also be ordered via our PGxome Custom Panel tool.

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

For Reflex to PGxome pricing click here.

Turnaround Time

18 days on average for standard orders or 14 days on average for STAT orders.

Once a specimen has started the testing process in our lab, the most accurate prediction of TAT will be displayed in the myPrevent portal as an Estimated Report Date (ERD) range. We calculate the ERD for each specimen as testing progresses; therefore the ERD range may differ from our published average TAT. View more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

Clinical Features and Genetics

Clinical Features

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.

Genetics

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.

Clinical Sensitivity - Sequencing with CNV PGxome

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).

Testing Strategy

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.

Since this test is performed using exome capture probes, a reflex to any of our exome based tests is available (PGxome, PGxome Custom Panels).

Indications for Test

Patients exhibiting ketotic or non-ketotic hypoglycemia without a known cause are good candidates for this panel. Patients with congenital hyperinsulinism are not good candidates for this panel, and may instead consider our Congenital Hyperinsulinism NextGen Sequencing Panel. Molecular testing is useful to confirm a clinical diagnosis of an inborn error of metabolism causing the observed hypoglycemic episodes, or rule out such causes in cases of idiopathic ketotic hypoglycemia (IKH).

Diseases

Name Inheritance OMIM ID
3-Hydroxy-3-Methylglutaryl-CoA Lyase Deficiency AR 246450
Alpha-Methylacetoacetic Aciduria AR 203750
Carnitine-Acylcarnitine Translocase Deficiency AR 212138
Charcot-Marie-Tooth disease, axonal, type 2EE AR 618400
Combined Malonic And Methylmalonic Aciduria AR 614265
Congenital Disorder of Glycosylation Type It AR 614921
Deficiency Of 3-Hydroxyacyl-CoA Dehydrogenase AR 231530
Diabetes Mellitus, Noninsulin-Dependent AD 125853
Erythrocyte Lactate Transporter Defect AD 245340
Familial Hypertrophic Cardiomyopathy 6 AD 600858
Fanconi-Bickel Syndrome AR 227810
Fructose-Biphosphatase Deficiency AR 229700
Galactosemia AR 230400
Glucocorticoid deficiency 4, with or without mineralocorticoid deficiency AR 614736
Glutaric Aciduria, Type 2 AR 231680
Glycerol Kinase Deficiency XL 307030
Glycogen Storage Disease 0, Liver AR 240600
Glycogen Storage Disease Of Heart, Lethal Congenital AD 261740
Glycogen Storage Disease Type Ia AR 232200
Glycogen Storage Disease Type Ib AR 232220
Glycogen Storage Disease Type Ic AR 232240
Glycogen Storage Disease Type III AR 232400
Glycogen Storage Disease Type IXa1 XL 306000
Glycogen Storage Disease Type IXc AR 613027
Glycogen Storage Disease Type VI AR 232700
Glycogen Storage DiseaseType IXb AR 261750
Hereditary Fructose Intolerance AR 229600
Hyperammonemia due to carbonic anhydrase VA deficiency AR 615751
Hyperinsulinemic Hypoglycemia, Familial, 4 AR 609975
Hyperinsulinemic Hypoglycemia, Familial, 7 AD 610021
Malonyl-CoA Decarboxylase Deficiency AR 248360
Medium-Chain Acyl-Coenzyme A Dehydrogenase Deficiency AR 201450
Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration AR 616878
Mitochondrial 3-Hydroxy-3-Methylglutaryl-CoA Synthase Deficiency AR 605911
Mitochondrial DNA-Depletion Syndrome 3, Hepatocerebral AR 251880
Monocarboxylate Transporter 1 Deficiency AD 616095
Navajo Neurohepatopathy AR 256810
Phosphoenolpyruvate Carboxykinase Deficiency, Cytosolic AR 261680
Phosphoenolpyruvate Carboxykinase Deficiency, Mitochondrial AR 261650
Portal hypertension, noncirrhotic AR 617068
Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal recessive 4 AR 617070
Pyruvate Carboxylase Deficiency AR 266150
Succinyl-CoA Acetoacetate Transferase Deficiency AR 245050
Systemic Carnitine Deficiency AR 212140
Very Long Chain Acyl-CoA Dehydrogenase Deficiency AR 201475
Wolff-Parkinson-White Pattern AD 194200

Related Test

Name
PGxome®
Congenital Hyperinsulinism Panel

Citations

  • Baker et al. 1993. PubMed ID: 26677512
  • Barbouth et al. 2006. PubMed ID: 16540753
  • Berry 2017. PubMed ID: 20301691
  • Choi et al. 2016. PubMed ID: 27103379
  • Coffee et al. 2006. PubMed ID: 17079880
  • Cryer et al. 2009. PubMed ID: 19088155
  • Davit-Spraul et al. 2011. PubMed ID: 21646031
  • Douillard et al. 2012. PubMed ID: 22587661
  • Esposito et al. 2010. PubMed ID: 20848650
  • Ferri et al. 2012. PubMed ID: 23430936
  • Ghosh et al. 2016. PubMed ID: 26718813
  • Human Gene Mutation Database (Biobase).
  • Kremer et al. 2016. PubMed ID: 26805782
  • Lalani et al. 2016. PubMed ID: 26805781
  • Lalani et al. 2018. PubMed ID: 29369572
  • Marles and Casiro. 1998. PubMed ID: 20401190
  • Santer et al. 2016. PubMed ID: 27101822
  • Saudubray and Charpentier. 2014. Clinical Phenotypes: Diagnosis/Algorithms. In: Valle D, Beaudet AL, Vogelstein B, et al., editors. New York, NY: McGraw-Hill. OMMBID.
  • Thornton et al. 2015. PubMed ID: 25957977

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

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