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Hypoglycemia, Hyperinsulinism and Ketone Metabolism Panel

50 gene panel that includes assessment of non-coding variants

Ideal for patients with a clinical suspicion of hypoglycemia and familial hyperinsulinism. The genes on this panel are included in the Comprehensive Metabolism Panel.

Analysis methods Availability Number of genes Test code CPT codes
4 weeks 50 GHC0056 SEQ 81405
SEQ 81406
SEQ 81407
DEL/DUP 81479


ICD codes
Commonly used ICD-10 code(s) when ordering the Hypoglycemia, Hyperinsulinism and Ketone Metabolism Panel

ICD-10 Disease
E16.1 Familial hyperinsulinism

Sample requirements:

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • Saliva (Oragene DNA OG-500 kit)

Label the sample tube with your patient’s name, date of birth and the date of sample collection. Note that we do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue.


Familial hyperinsulinism (FHI) is characterized by hypoglycemia that can have an onset neonatally or later during childhood. The disease presentation can vary considerably even within one family. It can present as severe with a very low glucose concentration or with variable and milder hypoglycemia. The clinical utility of this panel for familial hyperinsulinism is 50-60%. Most of the patients with familial hyperinsulinism have a mutated ABCC8 gene, while mutations in KCNJ11, GLUD1 and HFN4A have each been found in approximately 5% of patients. Congenital isolated hyperinsulinism is the most common cause of severe and persistent hypoglycemia in neonatal period. The prevalence has been estimated at 1:50,000 live births, with much higher numbers in certain more homogenous populations. Infants of diabetic mothers may present with a clinical picture identical to that of FHI and this panel has differential diagnostic power to diagnose cases with genetic causes of transient hypoglycemia in newborns. This panel also includes the Glycogen Storage Disorder Panel genes for differential diagnostic purposes, since hepatomegaly due to glycogen storage disorder might not be visible in the newborn period. Furthermore, the panel includes genes relevant in additional related phenotypes such as maturity onset diabetes of the young (MODY) or exercise-induced hyperinsulinism. Insulinoma and drug-induced hypoglycemia should also be considered in later-onset hyperinsulinism phenotypes.

Panel Content

Genes in the Hypoglycemia, Hyperinsulinism and Ketone Metabolism Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABCC8Hyperinsulinemic hypoglycemia, Diabetes, permanent neonatal, Hypoglycemia, leucine-induced, Diabetes mellitus, transient neonatalAD/AR128621
ACAT1Alpha-methylacetoacetic aciduriaAR3091
ACSF3Combined malonic and methylmalonic aciduriaAR1919
AGLGlycogen storage diseaseAR90243
ALDOAGlycogen storage diseaseAR28
ALDOBFructose intolerance, hereditaryAR3266
ENO3Glycogen storage diseaseAR35
EPM2AEpilepsy, progressive myoclonicAR1676
FBP1Fructose-1,6-bisphosphatase deficiencyAR1842
G6PCGlycogen storage diseaseAR35115
GAAGlycogen storage diseaseAR147558
GBE1Glycogen storage diseaseAR3470
GCKHyperinsulinemic hypoglycemia, familial, Diabetes mellitus, permanent neonatal, Maturity-onset diabetes of the young, type 2AD/AR179825
GLUD1Hyperammonemia-hyperinsulinism, Hyperinsulinemic hypoglycemiaAD/AR1438
GYG1Glycogen storage disease, Polyglucosan body myopathy 2AR815
GYS1Glycogen storage diseaseAR65
GYS2Glycogen storage diseaseAR1522
HADH3-hydroxyacyl-CoA dehydrogenase deficiencyAR1026
HMGCL3-hydroxy-3-methylglutaryl-CoA lyase deficiencyAR1360
HMGCS23-hydroxy-3-methylglutaryl-CoA synthase 2 deficiencyAR1127
HNF1AMaturity onset diabetes of the young, Renal cell carcinoma, nonpapillary clear cell, Liver adenomatosisAD72524
HNF4ACongenital hyperinsulinism, diazoxide-responsive, Maturity onset diabetes of the young, Fanconi renotubular syndrome 4 with maturity-onset diabetes of the youngAD30147
INSRHyperinsulinemic hypoglycemia, familial, Rabson-Mendenhall syndrome, Donohoe syndromeAD/AR44183
KCNJ11Hyperinsulinemic hypoglycemia, Diabetes, permanent neonatal, Diabetes mellitus, transient neonatal, Maturity-onset diabetes of the young 13, Paternally-inherited mutations can cause Focal adenomatous hyperplasiaAD/AR56173
LAMP2Danon diseaseXL5797
LDHAGlycogen storage diseaseAR19
MPV17Mitochondrial DNA depletion syndromeAR3542
NHLRC1Epilepsy, progressive myoclonicAR1570
OXCT1Succinyl CoA:3-oxoacid CoA transferase deficiencyAR732
PCPyruvate carboxylase deficiencyAR3140
PCK1Phosphoenolpyruvate carboxykinase 1 deficiencyAD/AR23
PDX1Pancreatic agenesis, Neonatal diabetes mellitus, Maturity-onset diabetes of the young, type 4, Lactic acidemia due to PDX1 deficiencyAD/AR1026
PFKMGlycogen storage diseaseAR1126
PGAM2Glycogen storage diseaseAR310
PGK1Phosphoglycerate kinase 1 deficiencyXL1526
PGM1Congenital disorder of glycosylationAR1030
PHKA1Glycogen storage diseaseXL78
PHKA2Glycogen storage diseaseXL25113
PHKBGlycogen storage diseaseAR725
PHKG2Glycogen storage diseaseAR731
PRKAG2Hypertrophic cardiomyopathy (HCM), Wolff-Parkinson-White syndrome, Glycogen storage disease of heart, lethal congenitalAD1756
PRKAG3Increased glyogen content in skeletal muscleAD11
PTF1APancreatic and cerebellar agenesis, Pancreatic agenesis 2AR415
PYGLGlycogen storage diseaseAR2044
PYGMGlycogen storage diseaseAR65165
RBCK1Polyglucosan body myopathyAR1014
SLC2A2Glycogen storage disease, Fanconi-Bickel syndrome, Neonatal diabetes mellitusAR2272
SLC16A1Hyperinsulinemic hypoglycemia, familial, Erythrocyte lactate transporter defect, Monocarboxylate transporter 1 deficiency, Myoclonic-atonic epilepsyAD/AR1214
SLC37A4Glycogen storage diseaseAR29109

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number

Panel Update

Genes added

  • ACSF3
  • AGL
  • ENO3
  • EPM2A
  • G6PC
  • GAA
  • GBE1
  • GYG1
  • GYS1
  • GYS2
  • LAMP2
  • LDHA
  • MPV17
  • NHLRC1
  • PC
  • PFKM
  • PGAM2
  • PGK1
  • PGM1
  • PHKA1
  • PHKA2
  • PHKB
  • PHKG2
  • PRKAG2
  • PRKAG3
  • PTF1A
  • PYGL
  • PYGM
  • RBCK1
  • SLC2A2
  • SLC37A4

Genes removed

  • PCK2

Test strength and Limitations

The strengths of this test include:

  • CAP and ISO-15189 accreditations covering all operations at GHC Genetics including all Whole Exome Sequencing, NGS panels and confirmatory testing
  • CLIA-certified personnel performing clinical testing in a CLIA-certified laboratory
  • Powerful sequencing technologies, advanced target enrichment methods and precision bioinformatics pipelines ensure superior analytical performance
  • Careful construction of clinically effective and scientifically justified gene panels
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publically available analytic validation demonstrating complete details of test performance
  • ~1,500 non-coding disease causing variants in GHC WES assay (please see below ‘Non-coding disease causing variants covered by this panel’)
  • Our rigorous variant classification based on modified ACMG variant classification scheme
  • Our systematic clinical interpretation workflow using proprietary software enabling accurate and traceable processing of NGS data
  • Our comprehensive clinical statements

Test limitations The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: *PPA2* (11, 12). Genes with partial, or whole gene, segmental duplications in the human genome are marked with an asterisk if they overlap with the UCSC pseudogene regions. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Repeat expansion disorders unless specifically mentioned
  • Non-coding variants deeper than ±20 base pairs from exon-intron boundary unless otherwise indicated (please see above Panel Content / non-coding variants covered by the panel).

This test may not reliably detect the following:
  • Low level mosaicism
  • Stretches of mononucleotide repeats
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments

The sensitivity of this test may be reduced if DNA is extracted by a laboratory other than GHC Genetics.

For additional information, please refer to the Test performance section and see our Analytic Validation.

Test Performance

The GHC Genetics panel covers classical genes associated with Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia (CPVT), cardiac arrest underlying cardiac condition, cardiac arrest cause unspecified, syncope and collapse, abnormal ECG, Long QT syndrome, arrhythmogenic right ventricular cardiomyopathy (ARVC) and Short QT syndrome. The genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sliced from our high-quality whole exome sequencing data. Please see our sequencing and detection performance table for different types of alterations at the whole exome level (Table).

Assays have been validated for different starting materials including EDTA-blood, isolated DNA (no FFPE), saliva and dry blood spots (filter card) and all provide high-quality results. The diagnostic yield varies substantially depending on the assay used, referring healthcare professional, hospital and country. GHC Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find a molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be a cost-effective first line test if your patient’s phenotype is suggestive of a specific mutation type.

Performance of GHC Genetics Whole Exome Sequencing (WES) assay.
All individual panels are sliced from WES data.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.65% (412,456/413,893) >99.99%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.94% (17,070/17,608) >99.99%
11-50 bps 99.07% (957/966) >99.99%
Copy number variants (exon level dels/dups)
Clinical samples (small CNVs, n=52)
1 exon level deletion 92.3% (24/26) NA
2 exons level deletion/duplication 100.0% (11/11) NA
3-7 exons level deletion/duplication 93.3% (14/15) NA
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
Simulated CNV detection
2 exons level deletion/duplication 90.98% (7,357/8,086) 99.96%
5 exons level deletion/duplication 98.63% (7,975/8,086) 99.98%
The performance presented above reached by WES with the following coverage metrics
Mean sequencing depth at exome level 174x
Nucleotides with >20x sequencing coverage (%) 99.4%

Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Detection of Del/Dup of several genes is by MLPA analysis (MS Holland). All genes are performed by CNV analysis through the genome depending on exon size, sequencing coverage and sequence content. We have validated the assays for different starting materials including isolated DNA from EDTA blood that provide high-quality results.

Bioinformatics & clinical interpretation

The sequencing data generated in our laboratory is analysed by our bioinformatic pipeline, integrating state-of-the art algorithms and industry-standard software solutions. We use also JSI medical systems software for sequencing data analysis. JSI medical systems is a certified system offering sophisticated bioinformatic software solutions covering a wide field of sequencing techniques.

Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results.

Every pathogenic or probably pathogenic variant is confirmed by the Sanger sequencing method. Sanger sequencing is also used occasionally with other variants reported in the statement. In the case of variant of uncertain significance (VUS) we do not recommend risk stratification based on the genetic finding. The analysis of detected variants was performed on the basis of the reference database of polymorphisms and international mutation databases: UMD, LOVD and ClinVar.

The consequence of variants in coding and splice regions are estimated using Alamut software. The Alamut database contains more than 28000 coding genes, non-protein coding genes and pseudogenes. This database (shared with the high throughput annotation engine for NGS data, Alamut Batch) is frequently updated. Information comes from different public databases such as NCBI, EBI, and UCSC, as well as other sources including gnomAD, ESP, Cosmic, ClinVar, or HGMD and CentoMD (for those a separate subscription from Qiagen/Biobase and Centogene respectively is required). Alamut Visual finds information about nucleotide conservation data through many vertebrates’ species, with the phastCons and phyloP scores, amino acid conservation data through orthologue alignments and information on protein domains.

Moreover, we integrate several missense variant pathogenicity prediction tools and algorithms such as SIFT, PolyPhen, AlignGVGD or MutationTaster. It also offers a window dedicated to the in silico study of variants’ effect on RNA splicing, allowing the assessment of their potential impact on splice junctions and visualization of cryptic or de novo splice sites. Impact on splicing regulation is also assessed.

Clinical interpretation

At GHC Genetics our geneticists and clinicians, who together evaluate the results from the sequence analysis pipeline in the context of phenotype information provided in the requisition form, prepare the clinical report. We recommend an interpretation of the findings of this molecular genetic analysis, including subsequent oncological consultation for the patient in the context of genetic counselling for the patient.

We strive to continuously monitor current genetic literature identifying new relevant information and findings and adapting them to our diagnostics. This enables relevant novel discoveries to be rapidly translated and adopted into our ongoing diagnostics development without delay. The undertaking of such comprehensive due diligence ensures that our diagnostic panels and clinical statements are the most up-to-date on the market.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Minor modifications were made to increase reproducibility of the variant classification and improve the clinical validity of the report. Our experience with tens of thousands of clinical cases analysed at our laboratories enables us to further develop the industry standard.

The final step in the analysis of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant three times at GHC Genetics. Reported variants of uncertain significance (VUS) are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for true positive call. Reported copy number variations with a size >10 exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen less than three times at GHC Genetics.

Our clinical statement includes tables for sequencing and copy number variants that include basic variant information (genomic coordinates, HGVS nomenclature, zygosity, allele frequencies, in silico predictions, OMIM phenotypes and classification of the variant). In addition, the statement includes detailed descriptions of the variant, gene and phenotype(s) including the role of the specific gene in human disease, the mutation profile, information about the gene’s variation in population cohorts and detailed information about related phenotypes. We also provide links to the references used, and mutation databases to help our customers further evaluate the reported findings if desired. The conclusion summarizes all of the existing information and provides our rationale for the classification of the variant.

Identification of pathogenic or likely pathogenic variants in dominant disorders or their combinations in different alleles in recessive disorders are considered molecular confirmation of the clinical diagnosis. In these cases, family member testing can be used for risk stratification within the family. In the case of variants of uncertain significance (VUS), we do not recommend family member risk stratification based on the VUS result. Furthermore, in the case of VUS, we do not recommend the use of genetic information in patient management or genetic counselling.

Our Clinical interpretation team analyses millions of variants from thousands of individuals with rare diseases. Thus, our database, and our understanding of variants and related phenotypes, is growing by leaps and bounds. Our laboratories are therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by GHC Genetics is re-classified, our laboratories will issue a follow-up statement to the original ordering health care provider at no additional cost.