Congenital Hyperinsulinism Sequencing Panel

  • Summary and Pricing
  • Clinical Features and Genetics
  • Citations
  • Methods
  • Ordering/Specimens
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NextGen Sequencing

Test Code Test Copy GenesCPT Code Copy CPT Codes
1939 ABCC8 81407 Add to Order
GCK 81406
GLUD1 81406
HADH 81479
HNF1A 81405
HNF4A 81406
KCNJ11 81403
SLC16A1 81479
UCP2 81479
Full Panel Price* $640.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
1939 Genes x (9) $640.00 81403, 81405, 81406(x3), 81407, 81479(x3) Add to Order
Pricing Comments

We are happy to accommodate requests for single genes 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 on our PGxome Custom Panel.

Parental targeted testing for all probands with uncertain, likely pathogenic or pathogenic variants in the ABCC8 and KCNJ11 genes are free of charge.

Targeted Testing

For ordering sequencing of targeted known variants, please proceed to our Targeted Variants landing page.

Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

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).

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Del/Dup via aCGH

Test Code Test Copy GenesPriceCPT Code Copy CPT Codes
600 ABCC8$990.00 81479 Add to Order
GCK$990.00 81479
GLUD1$990.00 81479
HADH$990.00 81479
HNF1A$990.00 81479
HNF4A$990.00 81479
KCNJ11$990.00 81479
SLC16A1$990.00 81479
UCP2$990.00 81479
Full Panel Price* $1290.00
Test Code Test Copy Genes Total Price CPT Codes Copy CPT Codes
600 Genes x (9) $1290.00 81479(x9) Add to Order
Pricing Comments

# of Genes Ordered

Total Price









Over 100

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Turnaround Time

The great majority of tests are completed within 20 days.

Clinical Sensitivity

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).

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Clinical Features

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).

Testing Strategy

This NextGen Sequencing Panel analyzes 9 genes that have been associated with CHI. For this NGS panel, the full coding regions, plus ~10bp of non-coding DNA flanking each exon, are sequenced for each of the genes listed below. Sequencing is accomplished by capturing specific regions with an optimized solution-based hybridization method, followed by massively parallel sequencing of the captured DNA fragments. Additional Sanger sequencing is performed for any regions not captured or with insufficient number of sequence reads. All pathogenic, undocumented and questionable variant calls are confirmed by Sanger sequencing.

Four of these genes can also be tested individually using our Sanger sequencing assays. Please see our test menu: ABCC8 (Test #1221), KCNJ11 (Test #1218), GCK (Test #1220) and GLUD1 (Test #1219).

Parental targeted testing for all probands with uncertain, likely pathogenic or pathogenic variants in the ABCC8 and KCNJ11 genes are free of charge.

Indications for Test

Candidates for this test are patients with CHI. This test especially aids in a differential diagnosis of similar phenotypes by analyzing multiple genes simultaneously.


Official Gene Symbol OMIM ID
ABCC8 600509
GCK 138079
GLUD1 138130
HADH 601609
HNF1A 142410
HNF4A 600281
KCNJ11 600937
SLC16A1 600682
UCP2 601693
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Related Tests

ABCC8-Related Congenital Hyperinsulinism via ABCC8 Gene Sequencing with CNV Detection
GLUD1-Related Congenital Hyperinsulinism via the GLUD1 Gene
UCP2-Related Congenital Hyperinsulinism via UCP2 Gene Sequencing with CNV Detection
Autism Spectrum Disorders and Intellectual Disability (ASD-ID) Comprehensive Sequencing Panel with CNV Detection
Hyperglycemia and Hypoglycemia via GCK Gene Sequencing with CNV Detection
Maturity Onset Diabetes of the Young (MODY) via the HNF1A Gene
Maturity Onset Diabetes of the Young (MODY) via the HNF4A Gene


Genetic Counselors
  • Arnoux J.B. et al. 2010. Early Human Development. 86: 287-94. PubMed ID: 20550977
  • Clayton PT, Eaton S, Aynsley-Green A, Edginton M, Hussain K, Krywawych S, Datta V, Malingre HE, Berger R, Berg IE van den. 2001. Hyperinsulinism in short-chain L-3-hydroxyacyl-CoA dehydrogenase deficiency reveals the importance of beta-oxidation in insulin secretion. J. Clin. Invest. 108: 457–465. PubMed ID: 11489939
  • Glaser B. 2003. Familial Hyperinsulinism. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301549
  • González-Barroso M.M. et al. 2008. Plos One. 3: e3850. PubMed ID: 19065272
  • Human Gene Mutation Database (Bio-base).
  • Kapoor R.R. et al. 2013. European Journal of Endocrinology / European Federation of Endocrine Societies. 168: 557-64. PubMed ID: 23345197
  • McDonald T.J., Ellard S. 2013. Annals of Clinical Biochemistry. 50: 403-15. PubMed ID: 23878349
  • Otonkoski T, Jiao H, Kaminen-Ahola N, Tapia-Paez I, Ullah MS, Parton LE, Schuit F, Quintens R, Sipilä I, Mayatepek E, Meissner T, Halestrap AP, et al. 2007. Physical exercise-induced hypoglycemia caused by failed silencing of monocarboxylate transporter 1 in pancreatic beta cells. Am. J. Hum. Genet. 81: 467–474. PubMed ID: 17701893
  • Snider K.E. et al. 2013. The Journal of Clinical Endocrinology and Metabolism. 98: E355-63. PubMed ID: 23275527
  • Stanescu DE, Hughes N, Kaplan B, Stanley CA, León DD De. 2012. Novel presentations of congenital hyperinsulinism due to mutations in the MODY genes: HNF1A and HNF4A. J. Clin. Endocrinol. Metab. 97: E2026–2030. PubMed ID: 22802087
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NextGen Sequencing using PG-Select Capture Probes

Test Procedure

We use a combination of Next Generation Sequencing (NGS) and Sanger sequencing technologies to cover the full coding regions of the listed genes plus ~10 bases of non-coding DNA flanking each exon.  As required, genomic DNA is extracted from the patient specimen.  For NGS, patient DNA corresponding to these regions is captured using an optimized set of DNA hybridization probes.  Captured DNA is sequenced using Illumina’s Reversible Dye Terminator (RDT) platform (Illumina, San Diego, CA, USA).  Regions with insufficient coverage by NGS are often covered by Sanger sequencing.

For Sanger sequencing, Polymerase Chain Reaction (PCR) is used to amplify targeted regions.  After purification of the PCR products, cycle sequencing is carried out using the ABI Big Dye Terminator v.3.0 kit.  PCR products are resolved by electrophoresis on an ABI 3730xl capillary sequencer.  In nearly all cases, cycle sequencing is performed separately in both the forward and reverse directions.

Patient DNA sequence is aligned to the genomic reference sequence for the indicated gene region(s). All differences from the reference sequences (sequence variants) are assigned to one of five interpretation categories, listed below, per ACMG Guidelines (Richards et al. 2015).

(1) Pathogenic Variants
(2) Likely Pathogenic Variants
(3) Variants of Uncertain Significance
(4) Likely Benign Variants
(5) Benign Variants

Human Genome Variation Society (HGVS) recommendations are used to describe sequence variants (  Rare variants and undocumented variants are nearly always classified as likely benign if there is no indication that they alter protein sequence or disrupt splicing.

Analytical Validity

As of March 2016, 6.36 Mb of sequence (83 genes, 1557 exons) generated in our lab was compared between Sanger and NextGen methodologies. We detected no differences between the two methods. The comparison involved 6400 total sequence variants (differences from the reference sequences). Of these, 6144 were nucleotide substitutions and 256 were insertions or deletions. About 65% of the variants were heterozygous and 35% homozygous. The insertions and deletions ranged in length from 1 to over 100 nucleotides.

In silico validation of insertions and deletions in 20 replicates of 5 genes was also performed. The validation included insertions and deletions of lengths between 1 and 100 nucleotides. Insertions tested in silico: 2200 between 1 and 5 nucleotides, 625 between 6 and 10 nucleotides, 29 between 11 and 20 nucleotides, 25 between 21 and 49 nucleotides, and 23 at or greater than 50 nucleotides, with the largest at 98 nucleotides. All insertions were detected. Deletions tested in silico: 1813 between 1 and 5 nucleotides, 97 between 6 and 10 nucleotides, 32 between 11 and 20 nucleotides, 20 between 21 and 49 nucleotides, and 39 at or greater than 50 nucleotides, with the largest at 96 nucleotides. All deletions less than 50 nucleotides in length were detected, 13 greater than 50 nucleotides in length were missed. Our standard NextGen sequence variant calling algorithms are generally not capable of detecting insertions (duplications) or heterozygous deletions greater than 100 nucleotides. Large homozygous deletions appear to be detectable.   

Analytical Limitations

Interpretation of the test results is limited by the information that is currently available.  Better interpretation should be possible in the future as more data and knowledge about human genetics and this specific disorder are accumulated.

When Sanger sequencing does not reveal any difference from the reference sequence, or when a sequence variant is homozygous, we cannot be certain that we were able to detect both patient alleles.  Occasionally, a patient may carry an allele which does not amplify, due to a large deletion or insertion.   In these cases, the report will contain no information about the second allele.  Our Sanger and NGS Sequencing tests are generally not capable of detecting Copy Number Variants (CNVs).

We sequence all coding exons for each given transcript, plus ~10 bp of flanking non-coding DNA for each exon.  Test reports contain no information about other portions of the gene, such as regulatory domains, deep intronic regions or any currently uncharacterized alternative exons.

In most cases, we are unable to determine the phase of sequence variants.  In particular, when we find two likely causative mutations for recessive disorders, we cannot be certain that the mutations are on different alleles.

Our ability to detect minor sequence variants due to somatic mosaicism is limited.  Sequence variants that are present in less than 50% of the patient’s nucleated cells may not be detected.

Runs of mononucleotide repeats (eg (A)n or (T)n) with n >8 in the reference sequence are generally not analyzed because of strand slippage during PCR.

Unless otherwise indicated, DNA sequence data is obtained from a specific cell-type (usually leukocytes from whole blood).   Test reports contain no information about the DNA sequence in other cell-types.

We cannot be certain that the reference sequences are correct.

Rare, low probability interpretations of sequencing results, such as for example the occurrence of de novo mutations in recessive disorders, are generally not included in the reports.

We have confidence in our ability to track a specimen once it has been received by PreventionGenetics.  However, we take no responsibility for any specimen labeling errors that occur before the sample arrives at PreventionGenetics.

Deletion/Duplication Testing via Array Comparative Genomic Hybridization

Test Procedure

Equal amounts of genomic DNA from the patient and a gender matched reference sample are amplified and labeled with Cy3 and Cy5 dyes, respectively. To prevent any sample cross contamination, a unique sample tracking control is added into each patient sample. Each labeled patient product is then purified, quantified, and combined with the same amount of reference product. The combined sample is loaded onto the designed array and hybridized for at least 22-42 hours at 65°C. Arrays are then washed and scanned immediately with 2.5 µM resolution. Only data for the gene(s) of interest for each patient are extracted and analyzed.

Analytical Validity

PreventionGenetics' high density gene-centric custom designed aCGH enables the detection of relatively small deletions and duplications within a single exon of a given gene or deletions and duplications encompassing the entire gene. PreventionGenetics has established and verified this test's accuracy and precision.

Analytical Limitations

Our dense probe coverage may allow detection of deletions/duplications down to 100 bp; however due to limitations and probe spacing this cannot be guaranteed across all exons of all genes. Therefore, some copy number changes smaller than 100-300 bp within a targeted large exon may not be detected by our array.

This array may not detect deletions and duplications present at low levels of mosaicism or those present in genes that have pseudogene copies or repeats elsewhere in the genome.

aCGH will not detect balanced translocations, inversions, or point mutations that may be responsible for the clinical phenotype.

Breakpoints, if occurring outside the targeted gene, may be hard to define.

The sensitivity of this assay may be reduced when DNA is extracted by an outside laboratory.

Order Kits

Ordering Options

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.
  • 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.


(Delivery accepted Monday - Saturday)

  • Collect 3 ml -5 ml (5 ml preferred) of whole blood in EDTA (purple top tube) or ACD (yellow top tube). For Test #500-DNA Banking only, collect 10 ml -20 ml of whole blood.
  • For small babies, we require a minimum of 1 ml of blood.
  • Only one blood tube is required for multiple tests.
  • Ship blood tubes at room temperature in an insulated container. Do not freeze blood.
  • During hot weather, include a frozen ice pack in the shipping container. Place a paper towel or other thin material between the ice pack and the blood tube.
  • In cold weather, include an unfrozen ice pack in the shipping container as insulation.
  • At room temperature, blood specimen is stable for up to 48 hours.
  • If refrigerated, blood specimen is stable for up to one week.
  • Label the tube with the patient name, date of birth and/or ID number.


(Delivery accepted Monday - Saturday)

  • Send in screw cap tube at least 5 µg -10 µg of purified DNA at a concentration of at least 20 µg/ml for NGS and Sanger tests and at least 5 µg of purified DNA at a concentration of at least 100 µg/ml for gene-centric aCGH, MLPA, and CMA tests, minimum 2 µg for limited specimens.
  • For requests requiring more than one test, send an additional 5 µg DNA per test ordered when possible.
  • DNA may be shipped at room temperature.
  • Label the tube with the composition of the solute, DNA concentration as well as the patient’s name, date of birth, and/or ID number.
  • We only accept genomic DNA for testing. We do NOT accept products of whole genome amplification reactions or other amplification reactions.


(Delivery preferred Monday - Thursday)

  • PreventionGenetics should be notified in advance of arrival of a cell culture.
  • Culture and send at least two T25 flasks of confluent cells.
  • Some panels may require additional flasks (dependent on size of genes, amount of Sanger sequencing required, etc.). Multiple test requests may also require additional flasks. Please contact us for details.
  • Send specimens in insulated, shatterproof container overnight.
  • Cell cultures may be shipped at room temperature or refrigerated.
  • Label the flasks with the patient name, date of birth, and/or ID number.
  • We strongly recommend maintaining a local back-up culture. We do not culture cells.
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