Epileptic Encephalopathy Panel

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

Test code: NE0401

The Blueprint Genetics Epileptic Encephalopathy Panel is an 84 gene test for genetic diagnostics of patients with clinical suspicion of epileptic encephalopathy.

The aetiology of the epileptic encephalopathies is variable; common causes of these anomalies are malformations, a metabolic disease or a genetic defect. Genetic testing is very useful in differential diagnosis of hereditary epileptic encephalopathies. Prenatal diagnosis is possible in families with a known genetic etiology. Depending of the specific syndrome and causative gene, epileptic encephalopathy can be inherited in an autosomal recessive, autosomal dominant or X-linked manner. Often, mutations occur as de novo. Genetic counseling is therefore very valuable to inform parents that their risk of having further children with similar disease is low. This panel is part of the Comprehensive epilepsy panel.

About Epileptic Encephalopathy

Epileptic encephalopathies are an epileptic condition characterized by epileptiform abnormalities associated with progressive cerebral dysfunction. They are a group of nosologies that are related to early age and manifest with EEG paroxysmal activity that is often aggressive, seizures that are commonly multi-form and intractable, cognitive, behavioural and neurological deficits that may be relentless and sometimes early death. Cognitive deficits and behavioural disturbances are presumed to be the main and sometimes the first and only unique manifestation of electrographic epileptic discharges in epileptic encephalopathies. In the classification of the International League Against Epilepsy eight age-related epileptic encephalopathy syndromes are recognized. These syndromes include early myoclonic encephalopathy and Ohtahara syndrome (also known as early infantile epileptic encephalopathy with suppression-bursts) in the neonatal period, West syndrome (also known as infantile spasms) and Dravet syndrome in infancy, myoclonic status in nonprogressive encephalopathies, and Lennox-Gastaut syndrome, Landau-Kleffner syndrome, and epilepsy with continuous spike waves during slow wave sleep in childhood and adolescences. Other epileptic syndromes such as migrating partial seizures in infancy and severe epilepsy with multiple independent spike foci may be reasonably added. A common feature is that these disorders are usually refractory to standard antiepileptic drugs (AEDs).

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 Epileptic Encephalopathy Panel and their clinical significance
Gene Associated phenotypes Inheritance ClinVar HGMD
ADAR Dyschromatosis symmetrica hereditaria, Aicardi-Goutières syndrome AD/AR 21 205
ADSL Adenylosuccinase deficiency AR 24 56
ALDH7A1 Epilepsy, pyridoxine-dependent AR 43 112
ALG13 Congenital disorder of glycosylation XL 5 7
AMT Glycine encephalopathy AR 26 95
ARHGEF9 Epileptic encephalopathy, early infantile XL 6 13
ARX Lissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardation XL 64 85
CACNA1A Migraine, familial hemiplegic, Episodic ataxia AD 93 203
CASK Mental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardation XL 67 87
CDKL5 Epileptic encephalopathy, early infantile, Rett syndrome, atypical, Angelman-like syndrome XL 266 280
CHD2 Epileptic encephalopathy, childhood-onset AD 57 43
CNTNAP2 Pitt-Hopkins like syndrome, Cortical dysplasia-focal epilepsy syndrome AR 35 67
CPT2 Carnitine palmitoyltransferase II deficiency AR 47 104
DCX Lissencephaly, Subcortical laminal heterotopia XL 126 138
DNM1* Epileptic encephalopathy, early infantile AD 19 19
DOCK7 Epilepitic encephalopathy AR 13 4
EEF1A2 Epileptic encephalopathy, early infantile, Mental retardation AD 10 10
FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects XL 102 220
FOXG1 Rett syndrome, congenital variant AD 81 124
GABRA1 Epileptic encephalopathy, early infantile, Epilepsy, childhood absence, Epilepsy, juvenile myoclonic AD 21 30
GABRB3 Epilepsy, childhood absence AD 14 41
GABRG2 Generalized epilepsy with febrile seizures plus, Familial febrile seizures, Dravet syndrome, Epilepsy, childhood absence AD 23 32
GAMT Guanidinoacetate methyltransferase deficiency AR 16 55
GLDC Glycine encephalopathy AR 95 423
GNAO1 Epileptic encephalopathy, early infantile AD 24 25
GPHN Hyperekplexia, Molybdenum cofactor deficiency AD/AR 25 20
GRIN2A Epilepsy, focal, with speech disorder AD 47 81
GRIN2B Epileptic encephalopathy, early infantile, Mental retardation AD 54 50
HCN1 Epileptic encephalopathy, early infantile AD 10 10
HEPACAM Megalencephalic leukoencephalopathy with subcortical cysts, remitting AD/AR 12 25
HNRNPU Intellectual disability and seizures AD 19 55
KCNA2 Epileptic encephalopathy, early infantile AD 10 12
KCNB1 Early infantile epileptic encephalopathy AD 13 12
KCNQ2 Epileptic encephalopathy, early infantile, Benign familial neonatal seizures, Myokymia AD 292 235
KCNQ3 Seizures, benign neonatal AD 16 17
KCNT1 Epilepsy, nocturnal frontal lobe AD 30 33
KIF1A Spastic paraplegia, Neuropathy, hereditary sensory, Mental retardation AD/AR 52 35
MBD5 Mental retardation AD 40 81
MECP2 Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardation XL 465 968
MEF2C Mental retardation AD 31 71
MOCS1 Molybdenum cofactor deficiency AR 7 32
MTHFR Homocystinuria due to MTHFR deficiency AR 57 119
NECAP1* Epileptic encephalopathy, early infantile AR 1 1
NRXN1 Pitt-Hopkins like syndrome, Schizophrenia AD/AR 80 304
PCDH19 Epileptic encephalopathy, early infantile XL 87 156
PIGA* Multiple congenital anomalies-hypotonia-seizures syndrome XL 23 17
PLCB1 Epileptic encephalopathy, early infantile AR 7 10
PNKP Epileptic encephalopathy, early infantile, Ataxia-oculomotor AR 31 17
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
PURA Mental retardation AD 47 26
RNASEH2A Aicardi-Goutières syndrome AR 13 21
RNASEH2B Aicardi-Goutières syndrome AR 10 40
SAMHD1 Aicardi-Goutières syndrome AR 22 51
SCN1A Migraine, familial hemiplegic, Epileptic encephalopathy, early infantile, Generalized epilepsy with febrile seizures plus AD 597 1459
SCN1B Atrial fibrillation, Brugada syndrome, Generalized epilepsy with febrile seizures plus AD 15 23
SCN2A Epileptic encephalopathy, early infantile, Seizures, benign familial infantile AD 139 220
SCN8A Cognitive impairment, Epileptic encephalopathy, early infantile AD 85 69
SIK1 Epileptic encephalopathy, early infantile AD 5 6
SLC2A1 Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndrome AD/AR 82 259
SLC6A8* Creatine deficiency syndrome XL 25 124
SLC9A6 Mental retardation, syndromic, Christianson XL 22 19
SLC12A5 Epileptic encephalopathy, early infantile AR 3 12
SLC13A5 Epileptic encephalopathy, early infantile AR 15 19
SLC19A3 Thiamine metabolism dysfunction syndrome AR 24 24
SLC25A22 Epileptic encephalopathy, early infantile AR 7 10
SLC35A2 Congenital disorder of glycosylation XL 13 15
SNAP25 Myasthenic syndrome, congenital AD 2 2
SPTAN1 Epileptic encephalopathy, early infantile AD 11 19
ST3GAL3 Epileptic encephalopathy, early infantile, Mental retardation AR 3 3
ST3GAL5 Ganglioside GM3 synthase deficiency AR 4 5
STXBP1 Epileptic encephalopathy, early infantile AD 102 172
SYN1 Epilepsy, with variable learning disabilities and behavior disorders XL 7 5
SYNGAP1 Mental retardation AD 54 63
SZT2 Epileptic encephalopathy, early infantile AR 9 9
TBC1D24 Deafness, Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome AD/AR 42 49
TCF4 Corneal dystrophy, Fuchs endothelial, Pitt-Hopkins syndrome AD 67 136
TREX1 Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndrome AD/AR 27 66
TSC1 Lymphangioleiomyomatosis, Tuberous sclerosis AD 106 336
TSC2 Lymphangioleiomyomatosis, Tuberous sclerosis AD 260 1093
UBE3A* Angelman syndrome AD 158 184
WDR45 Neurodegeneration with brain iron accumulation XL 28 67
WWOX Epileptic encephalopathy, early infantile, Spinocerebellar ataxia AR 30 36
ZEB2* Mowat-Wilson syndrome AD 117 270

*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
CDKL5 ChrX:18525053 c.-162-2A>G NM_003159.2 rs786204973
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
PNKP Chr19:50364799 c.1387-33_1386+49delCCTCCTCCCCTGACCCC NM_007254.3 rs752902474
TSC2 Chr16:2098067 c.-30+1G>C NM_000548.3 rs587778004

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 Epileptic Encephalopathy Panel that covers classical genes associated with epileptic encephalopathy. 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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