Metabolic Epilepsy Panel

  • bpg-method PLUS
  • bpg-method SEQ
  • bpg-method DEL/DUP

Test code: NE1601

The Blueprint Genetics Metabolic Epilepsy Panel is a 31 gene test for genetic diagnostics of patients with clinical suspicion of inherited metabolic disorder causing epileptic seizures.

The mainstay of 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. In several instances, it confirms the diagnosis suggested by biochemical analysis. Genetic testing is leading to expansion of the epileptic phenotypes of many of the genetic and indeed the 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 counseling. This panel is part of the Comprehensive Epilepsy Panel.

About Metabolic Epilepsy

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). As an example, GLUT1 deficiency syndrome is known to be a cause of drug-resistant childhood absence epilepsy and of adult-onset absence epilepsy with a normal CSF glucose. Molecular genetic analysis of the SLC2A1 gene is considered the standard criterion for diagnosis of GLUT1 deficiency syndrome. Epilepsy in GLUT1 deficiency is drug resistant and may be aggravated by fasting and by AEDs that inhibit GLUT1. GLUT1 deficiency is eminently treatable with the ketogenic diet, which should be commenced at the earliest opportunity and continued until at least adolescence.

Availability

Results in 3-4 weeks. We do not offer a maternal cell contamination (MCC) test at the moment. We offer prenatal testing only for cases where the maternal cell contamination studies (MCC) are done by a local genetic laboratory. Read more: http://blueprintgenetics.com/faqs/#prenatal

Genes in the Metabolic Epilepsy Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ADSL Adenylosuccinase deficiency AR 24 56
AGA Aspartylglucosaminuria AR 40 36
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency AR 10 69
ALDH7A1 Epilepsy, pyridoxine-dependent AR 43 112
AMT Glycine encephalopathy AR 26 95
ARG1 Hyperargininemia AR 16 54
BTD Biotinidase deficiency AR 183 235
DPYD 5-fluorouracil toxicity AD/AR 52 88
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 8 27
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 14
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 37 169
FH Hereditary leiomyomatosis and renal cell cancer AD/AR 142 174
GAMT Guanidinoacetate methyltransferase deficiency AR 16 55
GCDH Glutaric aciduria AR 64 205
GCH1 Dopa-Responsive Dystonia Hyperphenylalaninemia, BH4-deficient, GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia AD/AR 28 234
GLDC Glycine encephalopathy AR 95 423
GNE Inclusion body myopathy, Nonaka myopathy, Sialuria AD/AR 50 200
GPHN Hyperekplexia, Molybdenum cofactor deficiency AD/AR 25 20
L2HGDH L-2-hydroxyglutaric aciduria AR 11 75
MOCS1 Molybdenum cofactor deficiency AR 7 32
MTHFR Homocystinuria due to MTHFR deficiency AR 57 119
PGK1 Phosphoglycerate kinase 1 deficiency XL 15 26
PNPO Pyridoxamine 5'-phosphate oxidase deficiency AR 16 28
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 92 274
PRODH* Hyperprolinemia AR 41 10
PTS Hyperphenylalaninemia, BH4-deficient AR 16 90
QDPR Hyperphenylalaninemia, BH4-deficient AR 9 61
SLC2A1 Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndrome AD/AR 82 259
SLC25A15* Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome AR 21 36
SLC46A1 Folate malabsorption AR 17 20
SUOX Sulfocysteinuria AR 6 28

*Some regions of the gene are duplicated in the genome leading to limited sensitivity within the regions. Thus, low-quality variants are filtered out from the duplicated regions and only high-quality variants confirmed by other methods are reported out. Read more.

Gene, refers to HGNC approved gene symbol; Inheritance to inheritance patterns such as autosomal dominant (AD), autosomal recessive (AR) and X-linked (XL); ClinVar, refers to a number of variants in the gene classified as pathogenic or likely pathogenic in ClinVar (http://www.ncbi.nlm.nih.gov/clinvar/); HGMD, refers to a number of variants with possible disease association in the gene listed in Human Gene Mutation Database (HGMD, http://www.hgmd.cf.ac.uk/ac/). The list of associated (gene specific) phenotypes are generated from CDG (http://research.nhgri.nih.gov/CGD/) or Orphanet (http://www.orpha.net/) databases.

Gene Genomic location HG19 HGVS RefSeq RS-number
AMT Chr3:49459938 c.-55C>T NM_000481.3 rs386833677
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 Chr11:112098994 c.84-323A>T NM_000317.2 rs794726657

The strengths of this test include:

  • Blueprint Genetics is one of the few laboratories worldwide with CAP and ISO-15189 accreditation for NGS panels and CLIA certification
  • Superior sequencing quality
  • Careful selection of genes based on current literature, our experience and the most current mutation databases
  • Transparent and easy access to quality and performance data at the patient level that are accessible via our Nucleus portal
  • Transparent and reproducible analytical validation for each panel (see Test performance section; for complete details, see our Analytic Validation)
  • Sequencing and high resolution del/dup analysis available in one test
  • Inclusion of non-coding disease causing variants where clinically indicated (please see individual Panel descriptions)
  • Interpretation of variants following ACMG variant classification guidelines
  • Comprehensive clinical statement co-written by a PhD geneticist and a clinician specialist

 

This test does not detect the following:

  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Mitochondrial DNA variants
  • Variants in regulatory or non-coding regions of the gene unless otherwise indicated (please see Non-coding disease causing variants covered by the panel). This mean for instance intronic variants locating deeper than 15 nucleotides from the exon-intron boundary.

 

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
  • Disorders caused by long repetitive sequences (e.g. trinucleotide repeat expansions)

 

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.

Blueprint Genetics offers a comprehensive Metabolic Epilepsy Panel that covers classical genes associated with 4-hydroxybutyric aciduria, 6-pyruvoyl-tetrahydropterin synthase deficiency, adenylosuccinate lyase deficiency, argininemia, aspartylglucosaminuria, biotinidase deficiency, dihydropteridine reductase deficiency, dihydropyrimidine dehydrogenase deficiency, GLUT1 deficiency syndrome, GTP cyclohydrolase I deficiency, glutaryl-CoA dehydrogenase deficiency, glycine encephalopathy, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, guanidinoacetate methyltransferase deficiency, hereditary folate malabsorption, hereditary pheochromocytoma-paraganglioma, homocystinuria due to methylene tetrahydrofolate reductase deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, hyperprolinemia type 1, inherited metabolic disorder causing epileptic seizures, 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 are carefully selected based on the existing scientific evidence, our experience and most current mutation databases. Candidate genes are excluded from this first-line diagnostic test. The test does not recognise balanced translocations or complex inversions, and it may not detect low-level mosaicism. The test should not be used for analysis of sequence repeats or for diagnosis of disorders caused by mutations in the mitochondrial DNA.

Analytical validation is a continuous process at Blueprint Genetics. Our mission is to improve the quality of the sequencing process and each modification is followed by our standardized validation process. Average sensitivity and specificity in Blueprint NGS Panels is 99.3% and 99.9% for detecting SNPs. Sensitivity to for indels vary depending on the size of the alteration: 1-10bps (96.0%), 11-20 bps (88.4%) and 21-30 bps (66.7%). The longest detected indel was 46 bps by sequence analysis. Detection limit for Del/Dup (CNV) analysis varies through the genome depending on exon size, sequencing coverage and sequence content. The sensitivity is 71.5% for single exon deletions and duplications and 99% for three exons’ deletions and duplications. We have validated the assays for different starting materials including EDTA-blood, isolated DNA (no FFPE) and saliva that all provide high-quality results. The diagnostic yield varies substantially depending on the used assay, referring healthcare professional, hospital and country. Blueprint Genetics’ Plus Analysis (Seq+Del/Dup) maximizes the chance to find molecular genetic diagnosis for your patient although Sequence Analysis or Del/Dup Analysis may be cost-effective first line test if your patient’s phenotype is suggestive for a specific mutation profile.

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. The highest relevance in the reported variants is achieved through elimination of false positive findings based on variability data for thousands of publicly available human reference sequences and validation against our in-house curated mutation database as well as the most current and relevant human mutation databases. Reference databases currently used are the 1000 Genomes Project (http://www.1000genomes.org), the NHLBI GO Exome Sequencing Project (ESP; http://evs.gs.washington.edu/EVS), the Exome Aggregation Consortium (ExAC; http://exac.broadinstitute.org), ClinVar database of genotype-phenotype associations (http://www.ncbi.nlm.nih.gov/clinvar) and the Human Gene Mutation Database (http://www.hgmd.cf.ac.uk). The consequence of variants in coding and splice regions are estimated using the following in silico variant prediction tools: SIFT (http://sift.jcvi.org), Polyphen (http://genetics.bwh.harvard.edu/pph2/), and Mutation Taster (http://www.mutationtaster.org).

Through our online ordering and statement reporting system, Nucleus, the customer can access specific details of the analysis of the patient. This includes coverage and quality specifications and other relevant information on the analysis. This represents our mission to build fully transparent diagnostics where the customer gains easy access to crucial details of the analysis process.

In addition to our cutting-edge patented sequencing technology and proprietary bioinformatics pipeline, we also provide the customers with the best-informed clinical report on the market. Clinical interpretation requires fundamental clinical and genetic understanding. At Blueprint 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 statement. Our goal is to provide clinically meaningful statements that are understandable for all medical professionals, even without training in genetics.

Variants reported in the statement are always classified using the Blueprint Genetics Variant Classification Scheme modified from the ACMG guidelines (Richards et al. 2015), which has been developed by evaluating existing literature, databases and with thousands of clinical cases analyzed in our laboratory. Variant classification forms the corner stone of clinical interpretation and following patient management decisions. Our statement also includes allele frequencies in reference populations and in silico predictions. We also provide PubMed IDs to the articles or submission numbers to public databases that have been used in the interpretation of the detected variants. In our conclusion, we summarize all the existing information and provide our rationale for the classification of the variant.

A final component of the analysis is the Sanger confirmation of the variants classified as likely pathogenic or pathogenic. This does not only bring confidence to the results obtained by our NGS solution but establishes the mutation specific test for family members. 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. Furthermore, in the case VUS we do not recommend use of genetic information in patient management or genetic counseling. For some cases Blueprint Genetics offers a special free of charge service to investigate the role of identified VUS.

We constantly follow genetic literature adapting new relevant information and findings to our diagnostics. Relevant novel discoveries can be rapidly translated and adopted into our diagnostics without delay. These processes ensure that our diagnostic panels and clinical statements remain the most up-to-date on the market.

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ICD & CPT codes

CPT codes

SEQ 81479
DEL/DUP 81479

Accepted sample types

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 5μg
  • 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.

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