Epileptic Encephalopathy Panel

Updated
Summary
  • Is a 203 gene panel that includes assessment of non-coding variants.
  • In addition, it also includes the maternally inherited mitochondrial genome. Is ideal for patients with a clinical suspicion of epileptic encephalopathy. The genes on this panel are included on the Comprehensive Epilepsy Panel.

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

203

Test code

NE0401

Panel size

Large

CPT code *
81443(1)
* The CPT codes provided are based on AMA guidelines and are for informational purposes only. CPT coding is the sole responsibility of the billing party. Please direct any questions regarding coding to the payer being billed.

Summary

The Blueprint Genetics Epileptic Encephalopathy Panel (test code NE0401):

ICD codes

Commonly used ICD-10 code(s) when ordering the Epileptic Encephalopathy Panel

ICD-10 Disease
F84.2 Rett syndrome
H49.40 Progressive external ophthalmoplegia
G11.9 Hereditary ataxia
C94.2 Acute Megakaryoblastic Leukemia
K59.8 Chronic Intestinal Pseudoobstruction
T36.5 Adverse effect of aminoglycosides
G93.41 Metabolic Encephalopathy
H49.81 Kearns Sayre Syndrome
E88.42 MERFF Syndrome
H47.013 Nonarteritic Anterior Ischemic Optic Neuropathy
G60.2 Neuropathy in association with hereditary ataxia
G30 Alzheimer's Disease
G25.5 Chorea
G40 Epilepsy and recurrent seizures
I42 Cardiomyopathy
N26.9 Focal Segmental Glomerulosclerosis
G31.82 Leigh's Disease
H47.2 Leber's hereditary optic neuropathy
G71.3 Mitochondrial Myopathy
I42.1 Hypertrophic Cardiomyopathy
E11.9 Non-Insulin Dependent Diabetes Mellitus
Z86.74 Personal history of sudden cardiac arrest
H90.3 Sensorineural Hearing Loss

Sample Requirements

  • Blood (min. 1ml) in an EDTA tube
  • Extracted DNA, min. 2 μg in TE buffer or equivalent
  • Saliva (Please see Sample Requirements for accepted saliva kits)

Label the sample tube with your patient's name, date of birth and the date of sample collection.

We do not accept DNA samples isolated from formalin-fixed paraffin-embedded (FFPE) tissue. In addition, if the patient is affected with a hematological malignancy, DNA extracted from a non-hematological source (e.g. skin fibroblasts) is strongly recommended.

Please note that, in rare cases, mitochondrial genome (mtDNA) variants may not be detectable in blood or saliva in which case DNA extracted from post-mitotic tissue such as skeletal muscle may be a better option.

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

Gene Associated phenotypes Inheritance ClinVar HGMD
ABAT GABA-transaminase deficiency AR 11 12
ACTL6B Epilepitic encephalopathy AD/AR 1 3
ADAM22 Early infantile epileptic encephalopathy AR 2 3
ADAR Dyschromatosis symmetrica hereditaria, Aicardi-Goutières syndrome AD/AR 25 226
ADPRHL2 Neurodegeneration, childhood-onset, with brain atrophy AR 1
ADSL Adenylosuccinase deficiency AR 24 57
ALDH7A1 Epilepsy, pyridoxine-dependent AR 52 123
ALG13 Congenital disorder of glycosylation XL 5 12
AMT Glycine encephalopathy AR 42 95
AP2M1 Epilepitic encephalopathy AD
AP3B2 Epileptic encephalopathy, early infantile, 48 6 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
ATP6V1A Cutis laxa, autosomal recessive, type IID, Epileptic encephalopathy AD/AR 8 8
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
CACNA1B Dystonia 23, Early infantile epileptic encephalopathy AD/AR 28 3
CACNA1E Epileptic encephalopathy AD 8 6
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
CLTC 20 14
CNKSR2 Epileptic encephalopathy, X-linked mental retardation, Epilepsy and X-linked mental retardation XL 7 6
CNPY3 Epileptic encephalopathy AR 3 3
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
CYFIP2 Early infantile epileptic encephalopathy, Epilepsy AD 2 3
D2HGDH D-2-hydroxyglutaric aciduria 1 AR 13 33
DCX Lissencephaly, Subcortical laminal heterotopia XL 131 142
DENND5A Epileptic encephalopathy, early infantile, 49 AR 6 6
DNM1* Epileptic encephalopathy, early infantile AD 28 24
DNM1L Encephalopathy due to defective mitochondrial and peroxisomal fission 1 AD 17 20
DOCK7 Epilepitic encephalopathy AR 21 7
ECHS1 Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency AR 23 33
EEF1A2 Epileptic encephalopathy, early infantile, Mental retardation AD 17 12
ETHE1 Ethylmalonic encephalopathy AR 38 36
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
FRRS1L Epileptic encephalopathy, early infantile, 37 AR 9 6
GABBR2 Epileptic encephalopathy AD 5 5
GABRA1 Epileptic encephalopathy, early infantile, Epilepsy, childhood absence, Epilepsy, juvenile myoclonic AD 24 35
GABRB2 Epileptic encephalopathy AD 19 15
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
GLDC Glycine encephalopathy AR 139 425
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
KCNMA1 Paroxysmal nonkinesigenic dyskinesia 3 with or without generalized epilepsy (PNKD3), Cerebellar atrophy, developmental delay, and seizures (CADEDS) AD/AR 5 9
KCNQ2 Epileptic encephalopathy, early infantile, Benign familial neonatal seizures, Myokymia AD 335 274
KCNQ3 Seizures, benign neonatal AD 20 24
KCNQ5 Mental retardation, autosomal dominant 46 AD 6 5
KCNT1 Epilepsy, nocturnal frontal lobe AD 31 39
KCNT2 Epileptic encephalopathy AD 2 5
KCTD3 Epileptic encephalopathy AR 1 3
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
MBD5 Mental retardation AD 62 90
MDH2 Epileptic encephalopathy, early infantile, 51 AR 5 9
MECP2 Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardation XL 506 1039
MED17 Microcephaly, postnatal progressive, with seizures and brain atrophy AR 4 4
MEF2C Mental retardation AD 45 84
MOCS1* Molybdenum cofactor deficiency AR 7 35
MRPL44 Combined oxidative phosphorylation deficiency 16 AR 2 2
MT-ATP6 Neuropathy, ataxia, and retinitis pigmentosa, Leber hereditary optic neuropathy, Ataxia and polyneuropathy, adult-onset, Cardiomyopathy, infantile hypertrophic, Leigh syndrome, Striatonigral degeneration, infantile, mitochondrial Mitochondrial 19
MT-ATP8 Cardiomyopathy, apical hypertrophic, and neuropathy, Cardiomyopathy, infantile hypertrophic Mitochondrial 4
MT-CO1 Myoglobinuria, recurrent, Leber hereditary optic neuropathy, Sideroblastic anemia, Cytochrome C oxidase deficiency Mitochondrial 17
MT-CO2 Cytochrome c oxidase deficiency Mitochondrial 8
MT-CO3 Cytochrome c oxidase deficiency, Leber hereditary optic neuropathy Mitochondrial 9
MT-CYB Leber hereditary optic neuropathy Mitochondrial 69
MT-ND1 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Leber hereditary optic neuropathy, Leber optic atrophy and dystonia Mitochondrial 21
MT-ND2 Leber hereditary optic neuropathy, Mitochondrial complex I deficiency Mitochondrial 6
MT-ND3 Leber optic atrophy and dystonia, Mitochondrial complex I deficiency Mitochondrial 7
MT-ND4 Leber hereditary optic neuropathy, Leber optic atrophy and dystonia, Mitochondrial complex I deficiency Mitochondrial 11
MT-ND4L Leber hereditary optic neuropathy Mitochondrial 2
MT-ND5 Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Leber hereditary optic neuropathy, Mitochondrial complex I deficiency Mitochondrial 19
MT-ND6 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Oncocytoma, Leber hereditary optic neuropathy, Leber optic atrophy and dystonia, Mitochondrial complex I deficiency Mitochondrial 16
MT-RNR1 Deafness, mitochondrial Mitochondrial 3
MT-RNR2 Chloramphenicol toxicity/resistance Mitochondrial 2
MT-TA Leber hereditary optic neuropathy, Mitochondrial multisystemic disorder, Progressive external ophthalmoplegia, Dilated cardiomyopathy (DCM) Mitochondrial 4
MT-TC Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes Mitochondrial 3
MT-TD Mitochondrial multisystemic disorder Mitochondrial 1
MT-TE Diabetes-deafness syndrome, Mitochondrial myopathy, infantile, transient, Mitochondrial myopathy with diabetes Mitochondrial 5
MT-TF Myoclonic epilepsy with ragged red fibers, Nephropathy, tubulointerstitial, Encephalopathy, mitochondrial, Epilepsy, mitochondrial, Myopathy, mitochondrial, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Mitochondrial 7
MT-TG Hypertrophic cardiomyopathy, Encephalopathy, Myopathy Mitochondrial 3
MT-TH Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Mitochondrial 4
MT-TI Progressive external ophthalmoplegia Mitochondrial 7
MT-TK Myoclonic epilepsy with ragged red fibers Mitochondrial 5
MT-TL1 Cytochrome c oxidase deficiency, Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Diabetes-deafness syndrome, Cyclic vomiting syndrome, SIDS, susceptibility to Mitochondrial 14
MT-TL2 Progressive external ophthalmoplegia, Mitochondrial multisystemic disorder Mitochondrial 5
MT-TM Mitochondrial Myopathy, Leigh syndrome, Mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes Mitochondrial 1
MT-TN Progressive external ophthalmoplegia Mitochondrial 3
MT-TP Mitochondrial multisystemic disorder Mitochondrial 2
MT-TQ Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes, Encephalopathy Mitochondrial 2
MT-TR Dilated cardiomyopathy (DCM) Mitochondrial 2
MT-TS1 Myoclonic epilepsy with ragged red fibers, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes Mitochondrial 10
MT-TS2 Mitochondrial multisystemic disorder Mitochondrial 2
MT-TT Mitochondrial 5
MT-TV Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes Mitochondrial 3
MT-TW Leigh syndrome, Mitochondrial Myopathy Mitochondrial 8
MT-TY Mitochondrial 4
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
NDUFS6 Mitochondrial complex I deficiency AR 6 7
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
NEUROD2 Epileptic encephalopathy AD
NRXN1 Pitt-Hopkins like syndrome, Developmental delay with or without dysmorphic facies and autism AD/AR 99 311
NUBPL Mitochondrial complex I deficiency AR 9 10
PARS2 Alpers syndrome AR 3 6
PCDH19 Epileptic encephalopathy, early infantile XL 116 200
PHACTR1 Epileptic encephalopathy AD 4 2
PIGA* Multiple congenital anomalies-hypotonia-seizures syndrome XL 24 27
PIGB Epileptic encephalopathy AR
PIGP Epileptic encephalopathy, early infantile, 55 AR 2
PIGQ Epileptic encephalopathy AR 3 4
PIGS Epileptic encephalopathy AR
PLAA Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA) 3 3
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
PPP3CA Epilepitic encephalopathy AD 8 11
PROSC Epilepsy AR 7 12
PTPN23 Epileptic encephalopathy AR 1 4
PURA Mental retardation AD 74 47
RMND1* Combined oxidative phosphorylation deficiency AR 17 15
RNASEH2A Aicardi-Goutières syndrome AR 13 21
RNASEH2B Aicardi-Goutières syndrome AR 16 41
ROGDI Kohlschutter-Tonz syndrome AR 14 13
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
SCN3A Epilepsy, Epileptic encephalopathy AD 13 17
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 AD/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
SYNGAP1 Mental retardation AD 102 83
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
TRAK1 Epileptic encephalopathy AR 1 6
TREX1 Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndrome AD/AR 30 71
TRIM8 Epileptic encephalopathy AD 1 2
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
UBE3A* Angelman syndrome AD 176 202
UNC80 Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 AR 26 20
VARS Early-onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT), Encephalopathy, progressive AR 12 6
WARS2 Encephalopathy, mitochondrial AR 6 14
WDR45 Neurodegeneration with brain iron accumulation XL 46 78
WWOX Epileptic encephalopathy, early infantile, Spinocerebellar ataxia AR 43 45
ZEB2* Mowat-Wilson syndrome AD 154 287

* 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), and/or the gene has exons listed under Test limitations section that are not included in the panel as they are not sufficiently covered with high quality sequence 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), mitochondrial (mi), 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 Mitomap databases.

Non-coding variants covered by Epileptic Encephalopathy Panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ADSL Chr22:40742514 c.-49T>C NM_000026.2
AMT Chr3:49459938 c.-55C>T NM_000481.3 rs386833677
CACNA1A Chr19:13317355 c.*1500_*1504dupCTTTT NM_001127221.1
CACNA1A Chr19:13341036 c.5404-13G>A NM_001127221.1
CACNA1A Chr19:13617793 NM_001127221.1 rs965852937
CDKL5 ChrX:18525053 c.-162-2A>G NM_003159.2 rs786204973
D2HGDH Chr2:242680425 c.293-23A>G NM_152783.3
ETHE1 Chr19:44031407 NM_014297.3
FGF12 Chr3:191857076 c.*4722T>C NM_021032.4
FLNA ChrX:153581587 c.6023-27_6023-16delTGACTGACAGCC NM_001110556.1
GABRA1 Chr5:161274418 c.-248+1G>T NM_000806.5
GABRB3 Chr15:27018162 c.-53G>T NM_000814.5
GABRB3 Chr15:27019011 c.-902A>T NM_000814.5
GABRB3 Chr15:27020313 c.-2204G>A NM_000814.5
GABRB3 Chr15:27020399 c.-2290T>C NM_000814.5 rs546389769
GAMT Chr19:1399508 c.391+15G>T NM_138924.2 rs367567416
MEF2C Chr5:88179125 c.-510_-497delTCTTCCTCCTCCTC NM_002397.4
MOCS1 Chr6:39874534 c.*365_*366delAG NM_005943.5 rs397518419
MOCS1 Chr6:39876810 c.*7+6T>C NM_005943.5
MOCS1 Chr6:39894006 c.251-418delT NM_005943.5
MTHFR Chr1:11850973 c.1753-18G>A NM_005957.4 rs777661576
MTHFR Chr1:11863212 c.-13-28_-13-27delCT NM_005957.4 rs786204005
NDUFAF6 Chr8:96046914 c.298-768T>C NM_152416.3 rs575462405
NDUFAF6 Chr8:96048588 c.420+784C>T NM_152416.3 rs749738738
PNKP Chr19:50364799 c.1387-33_1386+49delCCTCCTCCCCTGACCCC NM_007254.3 rs752902474
RNASEH2B Chr13:51501530 c.65-13G>A NM_024570.3
RNASEH2B Chr13:51519550 c.511-13G>A NM_024570.3
ROGDI Chr16:4852483 c.46-30_45+37delGGCGGGGC NM_024589.2 rs786205125
SCN1A Chr2:166848946 c.4820-14T>G NM_006920.4
SCN1A Chr2:166854699 c.4306-14T>G NM_006920.4
SCN1A Chr2:166908215 c.964+14T>G NM_006920.4 rs794726837
SCN1A Chr2:166911289 c.474-13T>A NM_006920.4 rs1057520357
SERAC1 Chr6:158576548 c.92-165C>T NM_032861.3
SERAC1 Chr6:158576622 c.92-239G>C NM_032861.3
SLC19A3 Chr2:228560811 c.980-14A>G NM_025243.3 rs200542114
SLC2A1 Chr1:43395462 c.680-11G>A NM_006516.2
SLC2A1 Chr1:43424429 c.-107G>A NM_006516.2
SPTAN1 Chr9:131390187 c.6690-17G>A NM_001130438.2 rs796053325
TBCD Chr17:80851411 c.1564-12C>G NM_005993.4
TSC1 Chr9:135800306 c.363+668G>A NM_000368.4
TSC2 Chr16:2098067 c.-30+1G>C NM_000548.3 rs587778004
TSC2 Chr16:2106052 c.600-145C>T NM_000548.3
TSC2 Chr16:2107460 c.848+281C>T NM_000548.3 rs45517132
TSC2 Chr16:2110656 c.976-15G>A NM_000548.3 rs45517150
TSC2 Chr16:2127477 c.2838-122G>A NM_000548.3
TSC2 Chr16:2138031 c.5069-18A>G NM_000548.3 rs45484794
TTC19 Chr17:15903121 c.-42G>T NM_017775.3 rs769078093
WDR45 ChrX:48934430 c.236-18A>G NM_007075.3
ZEB2 Chr2:145274987 c.-69-1G>A NM_014795.3
ZEB2 Chr2:145274988 c.-69-2A>C NM_014795.3

Added and removed genes from the panel

Genes added Genes removed
MT-ATP6
MT-ATP8
MT-CO1
MT-CO2
MT-CO3
MT-CYB
MT-ND1
MT-ND2
MT-ND3
MT-ND4
MT-ND4L
MT-ND5
MT-ND6
MT-RNR1
MT-RNR2
MT-TA
MT-TC
MT-TD
MT-TE
MT-TF
MT-TG
MT-TH
MT-TI
MT-TK
MT-TL1
MT-TL2
MT-TM
MT-TN
MT-TP
MT-TQ
MT-TR
MT-TS1
MT-TS2
MT-TT
MT-TV
MT-TW
MT-TY

Test Strengths

The strengths of this test include:
  • CAP accredited laboratory
  • 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
  • Some of the panels include the whole mitochondrial genome (please see the Panel Content section)
  • Our Nucleus online portal providing transparent and easy access to quality and performance data at the patient level
  • Our publicly available analytic validation demonstrating complete details of test performance
  • ~2,000 non-coding disease causing variants in our clinical grade NGS assay for panels (please see ‘Non-coding disease causing variants covered by this panel’ in the Panel Content section)
  • Our rigorous 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

The following exons are not included in the panel as they are not sufficiently covered with high quality sequence reads: GABRG2 (NM_198903:6). 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).

This test does not detect the following:
  • Complex inversions
  • Gene conversions
  • Balanced translocations
  • Some of the panels include the whole mitochondrial genome but not all (please see the Panel Content section)
  • 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 in nuclear genes (variant with a minor allele fraction of 14.6% is detected with 90% probability)
  • Stretches of mononucleotide repeats
  • Low level heteroplasmy in mtDNA (>90% are detected at 5% level)
  • Indels larger than 50bp
  • Single exon deletions or duplications
  • Variants within pseudogene regions/duplicated segments
  • Some disease causing variants present in mtDNA are not detectable from blood, thus post-mitotic tissue such as skeletal muscle may be required for establishing molecular diagnosis.

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 genes on the panel have been carefully selected based on scientific literature, mutation databases and our experience.

Our panels are sectioned from our high-quality, clinical grade NGS assay. Please see our sequencing and detection performance table for details regarding our ability to detect different types of alterations (Table).

Assays have been validated for various sample types including EDTA-blood, isolated DNA (excluding from formalin fixed paraffin embedded tissue), saliva and dry blood spots (filter cards). These sample types were selected in order to maximize the likelihood for high-quality DNA yield. The diagnostic yield varies depending on the assay used, referring healthcare professional, hospital and country. Plus analysis increases the likelihood of finding a genetic diagnosis for your patient, as large deletions and duplications cannot be detected using sequence analysis alone. Blueprint Genetics’ Plus Analysis is a combination of both sequencing and deletion/duplication (copy number variant (CNV)) analysis.

Performance of Blueprint Genetics high-quality, clinical grade NGS sequencing assay for panels.

Sensitivity % (TP/(TP+FN) Specificity %
Single nucleotide variants 99.89% (99,153/99,266) >99.9999%
Insertions, deletions and indels by sequence analysis
1-10 bps 96.9% (7,563/7,806) >99.9999%
11-50 bps 99.13% (2,524/2,546) >99.9999%
Copy number variants (exon level dels/dups)
1 exon level deletion (heterozygous) 100% (20/20) NA
1 exon level deletion (homozygous) 100% (5/5) NA
1 exon level deletion (het or homo) 100% (25/25) NA
2-7 exon level deletion (het or homo) 100% (44/44) NA
1-9 exon level duplication (het or homo) 75% (6/8) NA
Simulated CNV detection
5 exons level deletion/duplication 98.7% 100.00%
Microdeletion/-duplication sdrs (large CNVs, n=37))
Size range (0.1-47 Mb) 100% (37/37)
     
The performance presented above reached by Blueprint Genetics high-quality, clinical grade NGS sequencing assay with the following coverage metrics
     
Mean sequencing depth 143X
Nucleotides with >20x sequencing coverage (%) 99.86%


Performance of Blueprint Genetics Mitochondrial Sequencing Assay.

Sensitivity % Specificity %
ANALYTIC VALIDATION (NA samples; n=4)
Single nucleotide variants
Heteroplasmic (45-100%) 100.0% (50/50) 100.0%
Heteroplasmic (35-45%) 100.0% (87/87) 100.0%
Heteroplasmic (25-35%) 100.0% (73/73) 100.0%
Heteroplasmic (15-25%) 100.0% (77/77) 100.0%
Heteroplasmic (10-15%) 100.0% (74/74) 100.0%
Heteroplasmic (5-10%) 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 50.0% (2/4) 100.0%
CLINICAL VALIDATION (n=76 samples)
All types
Single nucleotide variants n=2026 SNVs
Heteroplasmic (45-100%) 100.0% (1940/1940) 100.0%
Heteroplasmic (35-45%) 100.0% (4/4) 100.0%
Heteroplasmic (25-35%) 100.0% (3/3) 100.0%
Heteroplasmic (15-25%) 100.0% (3/3) 100.0%
Heteroplasmic (10-15%) 100.0% (9/9) 100.0%
Heteroplasmic (5-10%) 92.3% (12/13) 99.98%
Heteroplasmic (<5%) 88.9% (48/54) 99.93%
Insertions and deletions by sequence analysis n=40 indels
Heteroplasmic (45-100%) 1-10bp 100.0% (32/32) 100.0%
Heteroplasmic (5-45%) 1-10bp 100.0% (3/3) 100.0%
Heteroplasmic (<5%) 1-10bp 100.0% (5/5) 99,997%
SIMULATION DATA /(mitomap mutations)
Insertions, and deletions 1-24 bps by sequence analysis; n=17
Homoplasmic (100%) 1-24bp 100.0% (17/17) 99.98%
Heteroplasmic (50%) 100.0% (17/17) 99.99%
Heteroplasmic (25%) 100.0% (17/17) 100.0%
Heteroplasmic (20%) 100.0% (17/17) 100.0%
Heteroplasmic (15%) 100.0% (17/17) 100.0%
Heteroplasmic (10%) 94.1% (16/17) 100.0%
Heteroplasmic (5%) 94.1% (16/17) 100.0%
Copy number variants (separate artifical mutations; n=1500)
Homoplasmic (100%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (50%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (30%) 500 bp, 1kb, 5 kb 100.0% 100.0%
Heteroplasmic (20%) 500 bp, 1kb, 5 kb 99.7% 100.0%
Heteroplasmic (10%) 500 bp, 1kb, 5 kb 99.0% 100.0%
The performance presented above reached by following coverage metrics at assay level (n=66)
Mean of medians Median of medians
Mean sequencing depth MQ0 (clinical) 18224X 17366X
Nucleotides with >1000x MQ0 sequencing coverage (%) (clinical) 100%
rho zero cell line (=no mtDNA), mean sequencing depth 12X

Bioinformatics

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 and regulatory 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. If the test includes the mitochondrial genome the target region gene list contains the mitochondrial genes. 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 including, 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, ordering providers have access to the details of the analysis, including patient specific sequencing metrics, a gene level coverage plot and a list of regions with suboptimal coverage (<20X for nuclear genes and <1000X for mtDNA) if applicable. This reflects our mission to build fully transparent diagnostics where ordering providers can easily visualize the 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 ACMG guideline 2015.

The final step in the analysis is orthogonal confirmation. Sequence and copy number variants classified as pathogenic, likely pathogenic and variants of uncertain significance (VUS) are confirmed using bi-directional Sanger sequencing by orthogonal methods such as qPCR/ddPCR when they do not meet our stringent NGS quality metrics for a true positive call.

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, abstracts and variant databases used to help ordering providers 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. We do not recommend using variants of uncertain significance (VUS) for family member risk stratification or patient management. Genetic counseling is recommended.

Our interpretation team analyzes millions of variants from thousands of individuals with rare diseases. Our internal database and our understanding of variants and related phenotypes increases with every case analyzed. 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.

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