- Is a 128 gene panel that includes assessment of non-coding variants
Is ideal for patients with a clinical suspicion of epileptic encephalopathy. The genes on this panel are included on the Comprehensive Epilepsy Panel.
The Blueprint Genetics Epileptic Encephalopathy Panel (test code NE0401):
- Blood (min. 1ml) in an EDTA tube
- Extracted DNA, min. 2 μg in TE buffer or equivalent
- Saliva (Oragene DNA OG-500 kit/OGD-500 or OG-575 & OGD-575)
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. Read more about our sample requirements here.
Epileptic encephalopathies are characterized by epileptiform abnormalities associated with progressive cerebral dysfunction. They typically present at an 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). The aetiology of the epileptic encephalopathies is variable and includes malformations, metabolic disease and genetic conditions. Genetic testing is very useful in the 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 de novo.
Genes in the Epileptic Encephalopathy Panel and their clinical significance
|ADAR||Dyschromatosis symmetrica hereditaria, Aicardi-Goutières syndrome||AD/AR||25||226|
|ALG13||Congenital disorder of glycosylation||XL||5||12|
|APOPT1||Mitochondrial complex IV deficiency||AR||4||5|
|ARHGEF9||Epileptic encephalopathy, early infantile||XL||10||23|
|ARX||Lissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardation||XL||66||93|
|ASNS*||Asparagine synthetase deficiency||AR||21||26|
|BRAT1||Rigidity and multifocal seizure syndrome, lethal neonatal||AR||19||18|
|CACNA1A||Migraine, familial hemiplegic, Episodic ataxia, Spinocerebellar ataxia 6, Epileptic encephalopathy, early infantile, 42||AD||135||230|
|CASK||Mental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardation||XL||87||112|
|CDKL5||Epileptic encephalopathy, early infantile, Rett syndrome, atypical, Angelman-like syndrome||XL||312||331|
|CHD2||Epileptic encephalopathy, childhood-onset||AD||85||59|
|CLCN4||Mental retardation, X-linked 49||XL||21||17|
|CNTNAP2||Pitt-Hopkins like syndrome, Cortical dysplasia-focal epilepsy syndrome||AR||45||71|
|COX6B1||Mitochondrial complex IV deficiency||AR||2||3|
|CPT2||Carnitine palmitoyltransferase II deficiency||AR||72||111|
|D2HGDH||D-2-hydroxyglutaric aciduria 1||AR||13||33|
|DCX||Lissencephaly, Subcortical laminal heterotopia||XL||131||142|
|DNM1*||Epileptic encephalopathy, early infantile||AD||28||24|
|DNM1L||Encephalopathy due to defective mitochondrial and peroxisomal fission 1||AD||17||20|
|ECHS1||Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency||AR||23||33|
|EEF1A2||Epileptic encephalopathy, early infantile, Mental retardation||AD||17||12|
|FAR1*||Peroxisomal fatty acyl-CoA reductase 1 disorder||AR||4||4|
|FARS2||Combined oxidative phosphorylation deficiency 14, Spastic paraplegia 77, autosomal recessive||AR||17||20|
|FGF12||Epileptic encephalopathy, early infantile, 47||AD||6||10|
|FLNA||Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects||XL||133||257|
|FOXG1||Rett syndrome, congenital variant||AD||106||156|
|GABRA1||Epileptic encephalopathy, early infantile, Epilepsy, childhood absence, Epilepsy, juvenile myoclonic||AD||24||35|
|GABRB3||Epilepsy, childhood absence||AD||19||57|
|GABRG2||Generalized epilepsy with febrile seizures plus, Familial febrile seizures, Dravet syndrome, Epilepsy, childhood absence||AD||34||34|
|GAMT||Guanidinoacetate methyltransferase deficiency||AR||18||58|
|GNAO1||Epileptic encephalopathy, early infantile, Epileptic encephalopathy, early infantile, 17||AD||26||35|
|GPHN||Hyperekplexia, Molybdenum cofactor deficiency||AD/AR||35||20|
|GRIN1||Mental retardation, autosomal dominant 8||AD||37||38|
|GRIN2A||Epilepsy, focal, with speech disorder||AD||65||95|
|GRIN2B||Epileptic encephalopathy, early infantile, Mental retardation||AD||64||69|
|GTPBP3||Combined oxidative phosphorylation deficiency 23||AR||14||15|
|HCN1||Epileptic encephalopathy, early infantile||AD||13||14|
|HECW2||Neurodevelopmental disorder with hypotonia, seizures, and absent language||AD||9||10|
|HEPACAM||Megalencephalic leukoencephalopathy with subcortical cysts, remitting||AD/AR||12||26|
|HIBCH||3-hydroxyisobutryl-CoA hydrolase deficiency||AR||18||16|
|HNRNPU||Intellectual disability and seizures||AD||38||66|
|HTT||Huntington disease, Lopes-Maciel-Rodan syndrome (LOMARS)||AD/AR||8||7|
|KCNA2||Epileptic encephalopathy, early infantile||AD||15||21|
|KCNB1||Early infantile epileptic encephalopathy||AD||27||30|
|KCNQ2||Epileptic encephalopathy, early infantile, Benign familial neonatal seizures, Myokymia||AD||335||274|
|KCNQ3||Seizures, benign neonatal||AD||20||24|
|KCNT1||Epilepsy, nocturnal frontal lobe||AD||31||39|
|KIF1A||Spastic paraplegia, Neuropathy, hereditary sensory, Mental retardation||AD/AR||63||42|
|LRPPRC||Leigh syndrome, French-Canadian type||AR||55||17|
|LYRM7#||Mitochondrial complex III deficiency, nuclear type 8||AR||5||9|
|MECP2||Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardation||XL||506||1039|
|MOCS1*||Molybdenum cofactor deficiency||AR||7||35|
|MRPL44||Combined oxidative phosphorylation deficiency 16||AR||2||2|
|MTFMT||Combined oxidative phosphorylation deficiency 15||AR||15||16|
|MTHFR||Homocystinuria due to MTHFR deficiency||AR||65||122|
|NACC1||Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM)||AD||2||3|
|NDUFAF6||Mitochondrial complex I deficiency, Leigh syndrome||AR||18||10|
|NDUFS2||Mitochondrial complex I deficiency||AR||5||24|
|NDUFS4||Mitochondrial complex I deficiency, Leigh syndrome||AR||11||17|
|NDUFS7||Mitochondrial complex I deficiency, Leigh syndrome||AR||5||7|
|NDUFS8||Mitochondrial complex I deficiency, Leigh syndrome||AR||13||12|
|NDUFV1||Mitochondrial complex I deficiency||AR||19||35|
|NECAP1*||Epileptic encephalopathy, early infantile||AR||1||1|
|NRXN1||Pitt-Hopkins like syndrome, Schizophrenia||AD/AR||99||311|
|NUBPL||Mitochondrial complex I deficiency||AR||9||10|
|PCDH19||Epileptic encephalopathy, early infantile||XL||116||200|
|PIGA*||Multiple congenital anomalies-hypotonia-seizures syndrome||XL||24||27|
|PLCB1||Epileptic encephalopathy, early infantile||AR||8||10|
|PNKP||Epileptic encephalopathy, early infantile, Ataxia-oculomotor||AR||34||23|
|PNPO||Pyridoxamine 5'-phosphate oxidase deficiency||AR||15||31|
|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||89||290|
|RMND1*||Combined oxidative phosphorylation deficiency||AR||17||15|
|SAMHD1||Aicardi-Goutières syndrome, Chilblain lupus 2||AD/AR||25||56|
|SCN1A||Migraine, familial hemiplegic, Epileptic encephalopathy, early infantile, Generalized epilepsy with febrile seizures plus, Early infantile epileptic encephalopathy 6, Generalized epilepsy with febrile seizures plus, type 2 , Febrile seizures, familial 3A||AD||718||1585|
|SCN1B||Atrial fibrillation, Brugada syndrome, Generalized epilepsy with febrile seizures plus, Epilepsy, generalized, with febrile seizures plus, type 1, Epileptic encephalopathy, early infantile, 52||AD||16||31|
|SCN2A||Epileptic encephalopathy, early infantile, Seizures, benign familial infantile||AD||184||261|
|SCN8A||Cognitive impairment, Epileptic encephalopathy, early infantile||AD||91||93|
|SCO1||Mitochondrial complex IV deficiency||AR||6||5|
|SDHAF1||Mitochondrial complex II deficiency||AR||4||6|
|SERAC1||3-methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like syndrome||AR||22||52|
|SIK1||Epileptic encephalopathy, early infantile||AD||5||6|
|SLC12A5||Epileptic encephalopathy, early infantile||AR||6||14|
|SLC13A5||Epileptic encephalopathy, early infantile||AR||18||20|
|SLC19A3||Thiamine metabolism dysfunction syndrome||AR||32||37|
|SLC25A1||Combined D-2- and L-2-hydroxyglutaric aciduria||AR||8||24|
|SLC25A22||Epileptic encephalopathy, early infantile||AR||8||10|
|SLC2A1||Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndrome||AD/AR||106||275|
|SLC35A2||Congenital disorder of glycosylation||XL||16||16|
|SLC6A8*||Creatine deficiency syndrome||XL||38||133|
|SLC9A6||Mental retardation, syndromic, Christianson||XL||24||28|
|SNAP25||Myasthenic syndrome, congenital||AD||2||4|
|SPTAN1||Epileptic encephalopathy, early infantile||AD||16||40|
|ST3GAL3||Epileptic encephalopathy, early infantile, Mental retardation||AR||3||5|
|ST3GAL5||Ganglioside GM3 synthase deficiency||AR||10||5|
|STXBP1||Epileptic encephalopathy, early infantile||AD||140||190|
|SYN1||Epilepsy, with variable learning disabilities and behavior disorders||XL||12||8|
|SYNJ1||Epileptic encephalopathy, early infantile, 53, Parkinson disease 20, early-onset||AR||12||25|
|SZT2||Epileptic encephalopathy, early infantile||AR||20||24|
|TBC1D24||Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome, Deafness, autosomal dominant, 65, Myoclonic epilepsy, infantile, familial, Epileptic encephalopathy, early infantile, 16, Deafness, autosomal recessive 86||AD/AR||43||55|
|TBCD||Early-onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT)||AR||17||21|
|TBCE||Progressive encephalopathy with amyotrophy and optic atrophy (PEAMO)||AR||12||8|
|TBCK||Hypotonia, infantile, with psychomotor retardation and characteristic facies 3||AR||14||16|
|TCF4||Corneal dystrophy, Fuchs endothelial, Pitt-Hopkins syndrome||AD||105||146|
|TREX1||Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndrome||AD/AR||30||71|
|TSC1||Lymphangioleiomyomatosis, Tuberous sclerosis||AD||177||372|
|TSC2||Lymphangioleiomyomatosis, Tuberous sclerosis||AD||396||1195|
|TTC19||Mitochondrial complex III deficiency, nuclear type 2||AR||13||10|
|UBA5*||Epileptic encephalopathy, early infantile, 44, Spinocerebellar ataxia, autosomal recessive 24||AR||16||15|
|UNC80||Hypotonia, infantile, with psychomotor retardation and characteristic facies 2||AR||26||20|
|WDR45||Neurodegeneration with brain iron accumulation||XL||46||78|
|WWOX||Epileptic encephalopathy, early infantile, Spinocerebellar ataxia||AR||43||45|
* 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 Epileptic Encephalopathy Panel
|Gene||Genomic location HG19||HGVS||RefSeq||RS-number|
- 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
The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: GABRB2 (10). Genes with suboptimal coverage in our assay are marked with number sign (#) and 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. Gene is considered to have suboptimal coverage when >90% of the gene's target nucleotides are not covered at >20x with mapping quality score (MQ>20) reads. The technology may have limited sensitivity to detect variants in genes marked with these symbols (please see the Panel content table above).
- 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).
- Low level mosaicism (variant with a minor allele fraction of 14.6% is detected with 90% probability)
- 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 epileptic encephalopathy panel covers classical genes associated with epileptic encephalopathy. 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.
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 is orthogonal confirmation. Sequence variants classified as pathogenic, likely pathogenic and variants of uncertain significance
(VUS) are confirmed using bi-directional Sanger sequencing when they do not meet our stringent NGS quality metrics for a 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 (Plus analysis only).
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.
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.