Metabolic Epilepsy Panel

Last modified: Jun 12, 2018


  • Is a 41 gene panel that includes assessment of non-coding variants
  • Is ideal for patients with a clinical suspicion of an inherited metabolic disorder causing epileptic seizures. The genes on this panel are included on the Comprehensive Epilepsy Panel.

Analysis methods

  • PLUS
  • SEQ


3-4 weeks

Number of genes


Test code


CPT codes

SEQ 81404
SEQ 81405
SEQ 81406
DEL/DUP 81479


The Blueprint Genetics Metabolic Epilepsy Panel (test code NE1601):

  • Is a 41 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

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.

Epileptic seizures are a frequent symptom in metabolic disease, having been reported in more than 200 different inborn errors of metabolism (IEMs), and seizures are a relatively common reason for referral to the metabolic paediatrician or biochemical geneticist (PubMed: 22998469). The mainstay for the diagnosis of inborn errors of metabolism (IEMs) is biochemical investigation as metabolites may be assayed in blood, urine, or CSF. Genetic diagnosis constitutes the first line of investigation in those instances where there are no characteristic metabolites or diagnostic enzyme assay available or when the metabolite results are unclear. In several instances, genetic testing confirms the diagnosis suggested by biochemical analysis. Genetic testing is leading to the expansion of the epileptic phenotypes of many of the genetic and metabolic epilepsies. It is important to recognize and diagnose this group of disorders, since they may be treatable, and there are significant implications for genetic counselling.

Genes in the Metabolic Epilepsy Panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABAT GABA-transaminase deficiency AR 11 12
ADSL Adenylosuccinase deficiency AR 24 56
AGA Aspartylglucosaminuria AR 41 37
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency AR 14 69
ALDH7A1 Epilepsy, pyridoxine-dependent AR 50 113
AMT Glycine encephalopathy AR 25 95
ARG1 Hyperargininemia AR 17 54
BTD Biotinidase deficiency AR 180 236
D2HGDH D-2-hydroxyglutaric aciduria 1 AR 10 32
DHFR* Megaloblastic anemia due to dihydrofolate reductase deficiency AR 2 5
DNM1L Encephalopathy due to defective mitochondrial and peroxisomal fission 1 AD 18 20
DPYD 5-fluorouracil toxicity, Epilepsy, hearing loss, and mental retardation syndrome; EHLMRS AD/AR 54 85
DPYS Dihydropyriminidase deficiency AR 8 29
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 9 29
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 14
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 41 173
ETHE1 Ethylmalonic encephalopathy AR 36 35
FH Hereditary leiomyomatosis and renal cell cancer AD/AR 156 205
GAMT Guanidinoacetate methyltransferase deficiency AR 18 58
GCDH Glutaric aciduria AR 70 208
GCH1 Dopa-Responsive Dystonia Hyperphenylalaninemia, BH4-deficient, GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia AD/AR 39 236
GLDC Glycine encephalopathy AR 105 424
GNE Inclusion body myopathy, Nonaka myopathy, Sialuria AD/AR 58 201
GPHN Hyperekplexia, Molybdenum cofactor deficiency AD/AR 29 20
HIBCH 3-hydroxyisobutryl-CoA hydrolase deficiency AR 19 13
L2HGDH L-2-hydroxyglutaric aciduria AR 13 76
MOCS1* Molybdenum cofactor deficiency AR 7 35
MTHFR Homocystinuria due to MTHFR deficiency AR 63 120
PGK1 Phosphoglycerate kinase 1 deficiency XL 15 26
PNPO Pyridoxamine 5'-phosphate oxidase deficiency AR 15 30
POLG POLG-related ataxia neuropathy spectrum disorders, Sensory ataxia, dysarthria, and ophthalmoparesis, Alpers syndrome, Progressive external ophthalmoplegia with mitochondrial DNA deletions, Mitochondrial DNA depletion syndrome AD/AR 90 280
PRODH* Hyperprolinemia AR 44 10
PTS Hyperphenylalaninemia, BH4-deficient AR 19 92
QDPR Hyperphenylalaninemia, BH4-deficient AR 13 61
SERAC1 3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome AR 23 48
SLC2A1 Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndrome AD/AR 98 262
SLC25A1 Combined D-2- and L-2-hydroxyglutaric aciduria AR 8 16
SLC25A15* Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome AR 22 36
SLC39A8 Congenital disorder of glycosylation, type IIn AR 7 6
SLC46A1 Folate malabsorption AR 17 20
SUOX Sulfocysteinuria AR 6 28

* Some, or all, of the gene is duplicated in the genome. Read more.

# The gene has suboptimal coverage (means <90% of the gene’s target nucleotides are covered at >20x with mapping quality score (MQ>20) reads).

The sensitivity to detect variants may be limited in genes marked with an asterisk (*) or number sign (#)

Gene refers to the HGNC approved gene symbol; Inheritance refers to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), X-linked dominant (XLD) and X-linked recessive (XLR); ClinVar refers to the number of variants in the gene classified as pathogenic or likely pathogenic in this database (ClinVar); HGMD refers to the number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD). The list of associated, gene specific phenotypes are generated from CGD or Orphanet databases.

Non-coding variants covered by the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ADSL Chr22:40742514 c.-49T>C NM_000026.2
ALDH7A1 Chr5:125907053 c.696-502G>C NM_001182.4
AMT Chr3:49459938 c.-55C>T NM_000481.3 rs386833677
ARG1 Chr6:131901748 c.306-611T>C NM_000045.3
BTD Chr3:15687154 c.*159G>A NM_000060.2 rs530872564
D2HGDH Chr2:242680425 c.293-23A>G NM_152783.3
ETFDH Chr4:159593534 c.-75A>G NM_004453.2
GAMT Chr19:1399508 c.391+15G>T NM_138924.2 rs367567416
GCDH Chr19:13010271 c.1244-11A>G NM_000159.3
L2HGDH Chr14:50735527 c.906+354G>A NM_024884.2
MOCS1 Chr6:39874534 c.*365_*366delAG NM_005943.5 rs397518419
MTHFR Chr1:11863212 c.-13-28_-13-27delCT NM_005957.4 rs786204005
MTHFR Chr1:11850973 c.1753-18G>A NM_005957.4 rs777661576
PTS Chr11:112100215 c.164-716A>T NM_000317.2
PTS Chr11:112099026 c.84-291A>G NM_000317.2
PTS Chr11:112098994 c.84-323A>T NM_000317.2 rs794726657
QDPR Chr4:17500790 c.436+2552A>G NM_000320.2
SLC2A1 Chr1:43395462 c.680-11G>A NM_006516.2

Added and removed genes from the panel

Genes added Genes removed

Test strength

The strengths of this test include:
  • CAP and ISO-15189 accreditations covering all operations at Blueprint 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 Blueprint 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

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 Blueprint Genetics.

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

The Blueprint Genetics metabolic epilepsy panel covers classical genes associated with inherited metabolic disorder causing epileptic seizures, 4-hydroxybutyric aciduria, 6-pyruvoyl-tetrahydropterin synthase deficiency, adenylosuccinate lyase deficiency, argininemia, aspartylglucosaminuria, biotinidase deficiency, dihydropteridine reductase deficiency, dihydropyrimidine dehydrogenase deficiency, glutaryl-CoA dehydrogenase deficiency, glycine encephalopathy, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, GTP cyclohydrolase I deficiency, guanidinoacetate methyltransferase deficiency, GLUT1 deficiency syndrome, hereditary folate malabsorption, hereditary pheochromocytoma-paraganglioma, homocystinuria due to methylene tetrahydrofolate reductase deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, hyperprolinemia type 1, isolated sulfite oxidase deficiency, l-2-hydroxyglutaric aciduria, multiple acyl-CoA dehydrogenation deficiency, pyridoxal phosphate-responsive seizures, pyridoxine-dependent epilepsy, sialuria, sulfite oxidase deficiency due to molybdenum cofactor deficiency type A and sulfite oxidase deficiency due to molybdenum cofactor deficiency type C. 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. Blueprint 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 Blueprint 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%


The target region for each gene includes coding exons and ±20 base pairs from the exon-intron boundary. In addition, the panel includes non-coding variants if listed above (Non-coding variants covered by the panel). Some regions of the gene(s) may be removed from the panel if specifically mentioned in the ‘Test limitations” section above. The sequencing data generated in our laboratory is analyzed with our proprietary data analysis and annotation pipeline, integrating state-of-the art algorithms and industry-standard software solutions. Incorporation of rigorous quality control steps throughout the workflow of the pipeline ensures the consistency, validity and accuracy of results. Our pipeline is streamlined to maximize sensitivity without sacrificing specificity. We have incorporated a number of reference population databases and mutation databases such as, but not limited, to 1000 Genomes Project, gnomAD, ClinVar and HGMD into our clinical interpretation software to make the process effective and efficient. For missense variants, in silico variant prediction tools such as SIFT, PolyPhen, MutationTaster are used to assist with variant classification. Through our online ordering and statement reporting system, Nucleus, the customer has an access to details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with inadequate coverage if present. This reflects our mission to build fully transparent diagnostics where customers have easy access to crucial details of the analysis process.

Clinical interpretation

We provide customers with the most comprehensive clinical report available on the market. Clinical interpretation requires a fundamental understanding of clinical genetics and genetic principles. At Blueprint Genetics, our PhD molecular geneticists, medical geneticists and clinical consultants prepare the clinical statement together by evaluating the identified variants in the context of the phenotypic information provided in the requisition form. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals regardless of whether they have formal training in genetics.

Variant classification is the corner stone of clinical interpretation and resulting patient management decisions. Our classifications follow the Blueprint Genetics Variant Classification Schemes based on the ACMG guideline 2015. 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 analyzed at our laboratory allowed 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 at least three times at Blueprint Genetics. Reported variants of uncertain significance 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 Blueprint 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, congress abstracts 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 counseling. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

Our interpretation team analyzes 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 laboratory is therefore well positioned to re-classify previously reported variants as new information becomes available. If a variant previously reported by Blueprint Genetics is re-classified, our laboratory will issue a follow-up statement to the original ordering health care provider at no additional cost.