Epileptic Encephalopathy Panel

SEQmethod-seq-icon Our Sequence Analysis is based on a proprietary targeted sequencing method OS-Seq™ and offers panels targeted for genes associated with certain phenotypes. A standard way to analyze NGS data for finding the genetic cause for Mendelian disorders. Results in 21 days. DEL/DUPmethod-dup-icon Targeted Del/Dup (CNV) analysis is used to detect bigger disease causing deletions or duplications from the disease-associated genes. Results in 21 days. PLUSmethod-plus-icon Plus Analysis combines Sequence + Del/Dup (CNV) Analysis providing increased diagnostic yield in certain clinical conditions, where the underlying genetic defect may be detectable by either of the analysis methods. Results in 21 days.

Test code: NE0401

The Blueprint Genetics Epileptic Encephalopathy Panel is an 83 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).


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.

Genes in the Epileptic Encephalopathy Panel and their clinical significance
GeneAssociated phenotypesInheritanceClinVarHGMD
ADARDyschromatosis symmetrica hereditaria, Aicardi-Goutières syndromeAD/AR16202
ADSLAdenylosuccinase deficiencyAR2253
ALDH7A1Epilepsy, pyridoxine-dependentAR29110
ALG13Congenital disorder of glycosylationXL36
AMTGlycine encephalopathyAR2651
ARHGEF9Epileptic encephalopathy, early infantileXL311
ARXLissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardationXL5680
CACNA1AMigraine, familial hemiplegic, Episodic ataxiaAD55181
CASKMental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardationXL4380
CDKL5Epileptic encephalopathy, early infantile, Rett syndrome, atypical, Angelman-like syndromeXL222254
CHD2Epileptic encephalopathy, childhood-onsetAD4235
CNTNAP2Pitt-Hopkins like syndrome, Cortical dysplasia-focal epilepsy syndromeAR2260
CPT2Carnitine palmitoyltransferase II deficiencyAR36102
DCXLissencephaly, Subcortical laminal heterotopiaXL117138
DNM1*Epileptic encephalopathy, early infantileAD815
DOCK7Epilepitic encephalopathyAR114
EEF1A2Epileptic encephalopathy, early infantile, Mental retardationAD610
FLNAFrontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defectsXL86209
FOXG1Rett syndrome, congenital variantAD68115
GABRA1Epileptic encephalopathy, early infantile, Epilepsy, childhood absence, Epilepsy, juvenile myoclonicAD1535
GABRB3Epilepsy, childhood absenceAD546
GABRG2Generalized epilepsy with febrile seizures plus, Familial febrile seizures, Dravet syndrome, Epilepsy, childhood absenceAD2123
GAMTGuanidinoacetate methyltransferase deficiencyAR1253
GLDCGlycine encephalopathyAR89214
GNAO1Epileptic encephalopathy, early infantileAD1220
GPHNHyperekplexia, Molybdenum cofactor deficiencyAD/AR2520
GRIN2AEpilepsy, focal, with speech disorderAD3775
GRIN2BEpileptic encephalopathy, early infantile, Mental retardationAD3841
HCN1Epileptic encephalopathy, early infantileAD78
HEPACAMMegalencephalic leukoencephalopathy with subcortical cysts, remittingAD/AR923
HNRNPUIntellectual disability and seizuresAD434
KCNA2Epileptic encephalopathy, early infantileAD510
KCNB1Early infantile epileptic encephalopathyAD69
KCNQ2Epileptic encephalopathy, early infantile, Benign familial neonatal seizures, MyokymiaAD240205
KCNQ3Seizures, benign neonatalAD1117
KCNT1Epilepsy, nocturnal frontal lobeAD1628
KIF1ASpastic paraplegia, Neuropathy, hereditary sensory, Mental retardationAD/AR3527
MBD5Mental retardationAD2172
MECP2Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardationXL429937
MEF2CMental retardationAD2566
MOCS1Molybdenum cofactor deficiencyAR732
MTHFRHomocystinuria due to MTHFR deficiencyAR51127
NECAP1*Epileptic encephalopathy, early infantileAR11
NRXN1Pitt-Hopkins like syndrome, SchizophreniaAD/AR51290
PCDH19Epileptic encephalopathy, early infantileXL62141
PIGA*Multiple congenital anomalies-hypotonia-seizures syndromeXL1914
PLCB1Epileptic encephalopathy, early infantileAR510
PNKPEpileptic encephalopathy, early infantile, Ataxia-oculomotorAR2116
PNPOPyridoxamine 5'-phosphate oxidase deficiencyAR1428
PURAMental retardationAD3623
RNASEH2AAicardi-Goutières syndromeAR1221
RNASEH2BAicardi-Goutières syndromeAR539
SAMHD1Aicardi-Goutières syndromeAR2248
SCN1AMigraine, familial hemiplegic, Epileptic encephalopathy, early infantile, Generalized epilepsy with febrile seizures plusAD4761282
SCN1BAtrial fibrillation, Brugada syndrome, Generalized epilepsy with febrile seizures plusAD1118
SCN2AEpileptic encephalopathy, early infantile, Seizures, benign familial infantileAD86131
SCN8ACognitive impairment, Epileptic encephalopathy, early infantileAD5655
SIK1Epileptic encephalopathy, early infantileAD56
SLC2A1Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndromeAD/AR65253
SLC6A8*Creatine deficiency syndromeXL19127
SLC9A6Mental retardation, syndromic, ChristiansonXL2118
SLC12A5Epileptic encephalopathy, early infantileAR312
SLC13A5Epileptic encephalopathy, early infantileAR1014
SLC19A3Thiamine metabolism dysfunction syndromeAR1424
SLC25A22Epileptic encephalopathy, early infantileAR64
SLC35A2Congenital disorder of glycosylationXL713
SNAP25Myasthenic syndrome, congenitalAD23
SPTAN1Epileptic encephalopathy, early infantileAD1515
ST3GAL3Epileptic encephalopathy, early infantile, Mental retardationAR33
ST3GAL5Ganglioside GM3 synthase deficiencyAR44
STXBP1Epileptic encephalopathy, early infantileAD63156
SYN1Epilepsy, with variable learning disabilities and behavior disordersXL75
SYNGAP1Mental retardationAD2357
SZT2Epileptic encephalopathy, early infantileAR56
TBC1D24Deafness, Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndromeAD/AR2741
TCF4Corneal dystrophy, Fuchs endothelial, Pitt-Hopkins syndromeAD51129
TREX1Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndromeAD/AR2465
TSC1Lymphangioleiomyomatosis, Tuberous sclerosisAD61306
TSC2Lymphangioleiomyomatosis, Tuberous sclerosisAD141977
UBE3A*Angelman syndromeAD143170
WDR45Neurodegeneration with brain iron accumulationXL2056
WWOXEpileptic encephalopathy, early infantile, Spinocerebellar ataxiaAR1935
ZEB2*Mowat-Wilson syndromeAD104247
  • * 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.

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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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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