Beyond Paediatric Epilepsy panel

Last modified: Jun 12, 2018

Summary

  • Is a 283 gene panel that includes assessment of non-coding variants
  • Is ideal for certain paediatric epilepsy patients. The Paediatric Epilepsy? Look Beyond program offers eligible paediatric patients in European and Middle East Countries comprehensive genetic diagnostics for their epileptic disorder. The major inclusion criteria for this program are:

    1. Be ≥24 and ≤48 months old
    2. Unprovoked seizures started after 2 year of age
    3. One of the following signs/symptoms: history language delay or regression, motor impairments or regression (ataxia, abnormal gait, etc), EEG abnormality, MRI abnormality
    4. Have a copy of original medical data report from the physician or hospital assessing clinical condition of the patients
    5. Patient lives in Europe or the Middle East*

    Additional information about the program is available at blueprintgenetics.com/beyondpaediatricepilepsy/. The Blueprint Genetics Comprehensive Epilepsy Panel is used in this program.
    *To see the complete list of countries included in the programme please click here. Please note when ordering there is a limitation of 5 samples per institution for the year 2018

Analysis methods

  • PLUS
  • SEQ
  • DEL/DUP

Availability

3-4 weeks

Number of genes

283

Test code

NE2401

Panel size

Large

Summary

The Blueprint Genetics Beyond Paediatric Epilepsy panel (test code NE2401):

  • Is a 283 gene panel that includes assessment of selected non-coding disease-causing variants
  • Is available as PLUS analysis (sequencing analysis and deletion/duplication analysis), sequencing analysis only or deletion/duplication analysis only

ICD codes

Commonly used ICD-10 code(s) when ordering the Beyond Paediatric Epilepsy panel

ICD-10 Disease
G40.9 Epilepsy

Sample Requirements

  • EDTA blood, min. 1 ml
  • Purified DNA, min. 3μg
  • 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.

Epilepsy is defined by recurrent, unprovoked seizures due to abnormal, synchronized neuronal firing in the brain. It is one of the most common neurological conditions. Approximately 20-30 % of epilepsy cases are caused by acquired conditions, but the remaining 70-80 % of cases are believed to be due to one or more genetic factors. The epilepsies can be broadly grouped into three classes: genetic generalized epilepsy (formerly idiopathic generalized epilepsy); focal epilepsy; and epileptic encephalopathy. There are then several specific syndromes within each class defined by differences in specific seizure types, electroencephalogram (EEG) patterns, magnetic resonance imaging (MRI) findings and age of onset and disease progression. Epilepsy is also one of the features of many multisystemic genetic syndromes and often occurs in neurodegenerative diseases.

Genes in the Beyond Paediatric Epilepsy panel and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABAT GABA-transaminase deficiency AR 11 12
ABCD1* Adrenoleukodystrophy XL 83 659
ADAR Dyschromatosis symmetrica hereditaria, Aicardi-Goutières syndrome AD/AR 24 211
ADSL Adenylosuccinase deficiency AR 24 56
AFG3L2* Spastic ataxia, Spinocerebellar ataxia AD/AR 21 38
AGA Aspartylglucosaminuria AR 41 37
AIFM1 Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndrome XL 27 29
AIMP1 Leukodystrophy, hypomyelinating AR 4 5
ALDH3A2 Sjogren-Larsson syndrome AR 51 105
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency AR 14 69
ALDH7A1 Epilepsy, pyridoxine-dependent AR 50 113
ALG13 Congenital disorder of glycosylation XL 5 9
AMACR Alpha-methylacyl-CoA racemase deficiency, Bile acid synthesis defect AR 3 8
AMT Glycine encephalopathy AR 25 95
AP4B1 Spastic paraplegia 47, autosomal recessive AR 16 9
AP4E1 Stuttering, familial persistent, 1, Spastic paraplegia 51, autosomal recessive AR 5 12
AP4M1 Spastic paraplegia 50, autosomal recessive AR 16 9
AP4S1* Spastic paraplegia 52, autosomal recessive AR 7 8
APOPT1 Mitochondrial complex IV deficiency AR 4 5
ARG1 Hyperargininemia AR 17 54
ARHGEF9 Epileptic encephalopathy, early infantile XL 7 21
ARSA Metachromatic leukodystrophy AR 96 223
ARX Lissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardation XL 66 89
ASAH1 Spinal muscular atrophy with progressive myoclonic epilepsy, Farber lipogranulomatosis AR 13 71
ASNS* Asparagine synthetase deficiency AR 18 15
ASPA Aspartoacylase deficiency (Canavan disease) AR 39 102
ATP1A3 Alternating hemiplegia of childhood, Dystonia 12 AD 80 106
ATP13A2 Parkinson disease (Kufor-Rakeb syndrome) AR 20 37
ATRX Carpenter-Waziri syndrome, Alpha-thalassemia/mental retardation syndrome, Holmes-Gang syndrome, Juberg-Marsidi syndrome, Smith-Fineman-Myers syndrome, Mental retardation-hypotonic facies syndrome XL 59 163
BRAT1 Rigidity and multifocal seizure syndrome, lethal neonatal AR 17 17
BTD Biotinidase deficiency AR 180 236
CACNA1A Migraine, familial hemiplegic, Episodic ataxia, Spinocerebellar ataxia 6, Epileptic encephalopathy, early infantile, 42 AD 121 211
CACNA1H Childhood absence epilepsy AD 9 43
CACNB4 Episodic ataxia, Epilepsy, idiopathic generalized, susceptibility to, 9 AD 2 7
CASK Mental retardation and microcephaly with pontine and cerebellar hypoplasia, FG syndrome, Mental retardation XL 80 104
CASR Hypocalcemia, Neonatal hyperparathyroidism, Familial Hypocalciuric hypercalcemia with transient Neonatal hyperparathyroidism AD/AR 103 393
CC2D1A Mental retardation, autosomal recessive 3 AR 3 6
CDKL5 Epileptic encephalopathy, early infantile, Rett syndrome, atypical, Angelman-like syndrome XL 291 313
CERS1 Epilepsy, progressive myoclonic AR 11 1
CHD2 Epileptic encephalopathy, childhood-onset AD 70 48
CHRNA2 Epilepsy, nocturnal frontal lobe AD 3 6
CHRNA4 Epilepsy, nocturnal frontal lobe AD 7 15
CHRNB2 Epilepsy, nocturnal frontal lobe AD 9 13
CLCN2 Leukoencephalopathy with ataxia, Epilepsy AD/AR 25 23
CLCN4 Mental retardation, X-linked 49 XL 21 9
CLN3 Neuronal ceroid lipofuscinosis, type 3 AR 87 71
CLN5 Neuronal ceroid lipofuscinosis, type 5 AR 49 45
CLN6 Neuronal ceroid lipofuscinosis, type 6 AR 29 82
CLN8 Neuronal ceroid lipofuscinosis, type 8 AR 35 42
CNTNAP2 Pitt-Hopkins like syndrome, Cortical dysplasia-focal epilepsy syndrome AR 42 69
COL4A1 Schizencephaly, Anterior segment dysgenesis with cerebral involvement, Retinal artery tortuosity, Porencephaly, Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, Brain small vessel disease AD 56 99
COX6B1 Mitochondrial complex IV deficiency AR 2 3
COX15 Leigh syndrome, Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency AR 7 5
CPT2 Carnitine palmitoyltransferase II deficiency AR 48 107
CSF1R Leukoencephalopathy, diffuse hereditary, with spheroids AD 56 75
CSTB Epilepsy, progressive myoclonic AR 18 15
CTC1 Cerebroretinal microangiopathy with calcifications and cysts AR 16 30
CTSD Ceroid lipofuscinosis, neuronal AR 12 18
CTSF Neuronal ceroid lipofuscinosis AR 8 11
CUL4B Mental retardation, syndromic, Cabezas XL 23 37
CYP27A1 Cerebrotendinous xanthomatosis AR 61 108
D2HGDH D-2-hydroxyglutaric aciduria 1 AR 10 32
DARS Hypomyelination with brainstem and spinal cord involvement and leg spasticity AR 11 14
DARS2 Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation AR 27 60
DCX Lissencephaly, Subcortical laminal heterotopia XL 131 142
DDC Aromatic l-amino acid decarboxylase deficiency AR 12 51
DEPDC5 Epilepsy, familial focal, with variable foci AD 66 76
DHFR* Megaloblastic anemia due to dihydrofolate reductase deficiency AR 2 5
DNAJC5 Kufs disease,, Ceroid lipofuscinosis, neuronal 4, Parry AD 2 2
DNM1* Epileptic encephalopathy, early infantile AD 26 21
DNM1L Encephalopathy due to defective mitochondrial and peroxisomal fission 1 AD 18 20
DOCK7 Epilepitic encephalopathy AR 17 4
DPYD 5-fluorouracil toxicity, Epilepsy, hearing loss, and mental retardation syndrome; EHLMRS AD/AR 54 85
DPYS Dihydropyriminidase deficiency AR 8 29
EARS2 Combined oxidative phosphorylation deficiency AR 14 30
ECHS1 Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency AR 23 31
ECM1 Lipoid proteinosis AR 13 61
EEF1A2 Epileptic encephalopathy, early infantile, Mental retardation AD 12 11
EFHC1 Epilepsy, myoclonic juvenile, Epilepsy, severe intractable, Epilepsy, juvenile absence AD/AR 5 34
EIF2B1 Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy AR 7 9
EIF2B2 Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy AR 10 27
EIF2B3 Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy AR 6 22
EIF2B4 Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy AR 8 30
EIF2B5 Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy AR 21 96
EPM2A Epilepsy, progressive myoclonic AR 16 76
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 9 29
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 14
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 41 173
ETHE1 Ethylmalonic encephalopathy AR 36 35
FA2H Spastic paraplegia AR 17 41
FAM126A Leukodystrophy, hypomyelinating AR 8 12
FAR1* Peroxisomal fatty acyl-CoA reductase 1 disorder AR 4 4
FARS2 Combined oxidative phosphorylation deficiency 14, Spastic paraplegia 77, autosomal recessive AR 19 18
FGF12 Epileptic encephalopathy, early infantile, 47 AD 6 9
FH Hereditary leiomyomatosis and renal cell cancer AD/AR 156 205
FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects XL 119 235
FOLR1 Cerebral folate deficiency AR 10 27
FOXG1 Rett syndrome, congenital variant AD 99 146
FOXRED1 Leigh syndrome, Mitochondrial complex I deficiency AR 15 8
GABRA1 Epileptic encephalopathy, early infantile, Epilepsy, childhood absence, Epilepsy, juvenile myoclonic AD 23 32
GABRB2 Epileptic encephalopathy AD 19 14
GABRB3 Epilepsy, childhood absence AD 18 41
GABRG2 Generalized epilepsy with febrile seizures plus, Familial febrile seizures, Dravet syndrome, Epilepsy, childhood absence AD 32 32
GALC Krabbe disease AR 74 234
GAMT Guanidinoacetate methyltransferase deficiency AR 18 58
GCDH Glutaric aciduria AR 70 208
GCH1 Dopa-Responsive Dystonia Hyperphenylalaninemia, BH4-deficient, GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia AD/AR 39 236
GFAP Alexander disease AD 114 131
GFM1 Combined oxidative phosphorylation deficiency AR 18 18
GJC2 Spastic paraplegia, Lymphedema, hereditary, Leukodystrophy, hypomyelinating AD/AR 24 54
GLB1 GM1-gangliosidosis, Mucopolysaccharidosis (Morquio syndrome) AR 65 212
GLDC Glycine encephalopathy AR 105 424
GLRB Hyperekplexia 2 AR 3 18
GNAO1 Epileptic encephalopathy, early infantile, Epileptic encephalopathy, early infantile, 17 AD 25 27
GNB1 Mental retardation, autosomal dominant 42 AD 15 23
GNE Inclusion body myopathy, Nonaka myopathy, Sialuria AD/AR 58 201
GOSR2* Epilepsy, progessive myoclonic AR 5 2
GPHN Hyperekplexia, Molybdenum cofactor deficiency AD/AR 29 20
GRIA3 Mental retardation XL 12 21
GRIK2 Mental retardation, autosomal recessive 6 AR 2 7
GRIN1 Mental retardation, autosomal dominant 8 AD 35 27
GRIN2A Epilepsy, focal, with speech disorder AD 52 83
GRIN2B Epileptic encephalopathy, early infantile, Mental retardation AD 64 64
GRN Frontotemporal lobar degeneration with TDP43 inclusions, GRN-related, Neuronal ceroid lipofuscinosis AD/AR 36 175
GTPBP3 Combined oxidative phosphorylation deficiency 23 AR 14 15
HACE1 Spastic paraplegia and psychomotor retardation with or without seizures AR 10 11
HCN1 Epileptic encephalopathy, early infantile AD 11 11
HECW2 Neurodevelopmental disorder with hypotonia, seizures, and absent language AD 9 4
HEPACAM Megalencephalic leukoencephalopathy with subcortical cysts, remitting AD/AR 12 26
HIBCH 3-hydroxyisobutryl-CoA hydrolase deficiency AR 19 13
HNRNPU Intellectual disability and seizures AD 29 66
HSD17B10 17-beta-hydroxysteroid dehydrogenase X deficiency, Mental retardation, syndromic XL 10 14
HSPD1* Spastic paraplegia, Leukodystrophy, hypomyelinating AD/AR 4 4
HTRA1 Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 (CADASIL2), Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) AR 24 30
HTT Huntington disease AD/AR 8 7
IBA57 Multiple mitochondrial dysfunctions syndrome 3, Spastic paraplegia 74, autosomal recessive AR 4 13
IQSEC2 Mental retardation XL 48 52
KCNA1 Episodic ataxia/myokymia syndrome AD 24 41
KCNA2 Epileptic encephalopathy, early infantile AD 13 15
KCNB1 Early infantile epileptic encephalopathy AD 22 29
KCNC1 Epilepsy, progressive myoclonic AD 5 2
KCNH1 Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1 AD/AR 15 13
KCNQ2 Epileptic encephalopathy, early infantile, Benign familial neonatal seizures, Myokymia AD 324 245
KCNQ3 Seizures, benign neonatal AD 18 17
KCNT1 Epilepsy, nocturnal frontal lobe AD 33 37
KCTD7* Epilepsy, progressive myoclonic AR 13 17
KDM5C Mental retardation, syndromic, Claes-Jensen XL 43 54
KIF1A Spastic paraplegia, Neuropathy, hereditary sensory, Mental retardation AD/AR 58 39
L2HGDH L-2-hydroxyglutaric aciduria AR 13 76
LGI1 Epilepsy, familial temporal lobe AD 25 49
LMNB1 Leukodystrophy, demyelinating, adult-onset, autosomal dominant AD 2 34
LRPPRC Leigh syndrome, French-Canadian type AR 20 15
LYRM7# Mitochondrial complex III deficiency, nuclear type 8 AR 5 7
MAGI2 Nephrotic syndrome 15 AR 7 24
MARS2 Combined oxidative phosphorylation deficiency AR 8 5
MBD5 Mental retardation AD 48 87
MECP2 Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardation XL 471 984
MED12 Ohdo syndrome, Mental retardation, with Marfanoid habitus, FG syndrome, Opitz-Kaveggia syndrome, Lujan-Fryns syndrome XL 29 27
MEF2C Mental retardation AD 39 74
MFSD8 Ceroid lipofuscinosis, neuronal AR 25 46
MLC1 Megalencephalic leukoencephalopathy with subcortical cysts AR 30 108
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 63 120
MTOR Smith-Kingsmore syndrome AD 25 18
NACC1 Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM) AD 2 2
NDUFAF5 Mitochondrial complex I deficiency AR 10 11
NDUFAF6 Mitochondrial complex I deficiency, Leigh syndrome AR 18 8
NDUFS2 Mitochondrial complex I deficiency AR 5 22
NDUFS4 Mitochondrial complex I deficiency, Leigh syndrome AR 10 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 34
NECAP1* Epileptic encephalopathy, early infantile AR 1 1
NEU1 Sialidosis AR 22 60
NFU1 Multiple mitochondrial dysfunctions syndrome 1 AR 6 15
NHLRC1 Epilepsy, progressive myoclonic AR 15 70
NOTCH3 Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Lateral meningocele syndrome AD 85 342
NRXN1 Pitt-Hopkins like syndrome, Epilepsy, hearing loss, and mental retardation syndrome; EHLMRS AD/AR 81 306
NUBPL Mitochondrial complex I deficiency AR 10 9
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 142 157
OPHN1 Mental retardation, with cerebellar hypoplasia and distinctive facial appearance XL 25 36
PCDH19 Epileptic encephalopathy, early infantile XL 104 160
PGK1 Phosphoglycerate kinase 1 deficiency XL 15 26
PHF6 Borjeson-Forssman-Lehmann syndrome XL 20 29
PIGA* Multiple congenital anomalies-hypotonia-seizures syndrome XL 24 24
PIGN* Multiple congenital anomalies-hypotonia-seizures syndrome 1 AR 31 32
PIGO Hyperphosphatasia with mental retardation syndrome 2 AR 13 19
PIGT Multiple congenital anomalies-hypotonia-seizures syndrome 3 AR 9 11
PIGV Hyperphosphatasia with mental retardation syndrome 1 AR 8 16
PLCB1 Epileptic encephalopathy, early infantile AR 7 10
PLP1 Spastic paraplegia, Pelizaeus-Merzbacher disease XL 55 337
PNKP Epileptic encephalopathy, early infantile, Ataxia-oculomotor AR 34 17
PNPO Pyridoxamine 5'-phosphate oxidase deficiency AR 15 30
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 90 280
POLR3A Leukodystrophy, hypomyelinating AR 29 86
POLR3B Leukodystrophy, hypomyelinating AR 19 56
PPT1* Ceroid lipofuscinosis, neuronal AR 86 77
PRICKLE1 Epilepsy, progressive myoclonic AD/AR 3 14
PRIMA1 Epilepsy, nocturnal frontal lobe AR 1
PRODH* Hyperprolinemia AR 44 10
PRRT2 Episodic kinesigenic dyskinesia, Seizures, benign familial infantile, 2, Convulsions, familial infantile, with paroxysmal choreoathetosis AD 40 93
PSAP Krabbe disease, atypical, Metachromatic leukodystrophy due to saposin-b deficiency, Combined saposin deficiency, Gaucher disease, atypical, due to saposin C deficiency AR 18 26
PTS Hyperphenylalaninemia, BH4-deficient AR 19 92
PURA Mental retardation AD 66 42
PYCR2# Leukodystrophy, hypomyelinating 10 AR 10 12
QDPR Hyperphenylalaninemia, BH4-deficient AR 13 61
RAB39B Waisman parkinsonism-mental retardation syndrome, Mental retardation XL 6 17
RARS Leukodystrophy, hypomyelinating 9 AD 12 10
RELN Lissencephaly, Epilepsy, familial temporal lobe AD/AR 23 41
RMND1* Combined oxidative phosphorylation deficiency AR 18 15
RNASEH2A Aicardi-Goutières syndrome AR 13 21
RNASEH2B Aicardi-Goutières syndrome AR 13 40
RNASEH2C Aicardi-Goutières syndrome AR 6 14
RNASET2 Leukoencephalopathy, cystic, without megalencephaly AR 7 10
RNF216* Cerebellar ataxia and hypogonadotropic hypogonadism (Gordon Holmes syndrome) AR 10 12
ROGDI Kohlschutter-Tonz syndrome AR 11 13
SAMHD1 Aicardi-Goutières syndrome, Chilblain lupus 2 AR 23 55
SCARB2 Epilepsy, progressive myoclonic AR 23 24
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 654 1489
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 15 29
SCN2A Epileptic encephalopathy, early infantile, Seizures, benign familial infantile AD 173 226
SCN8A Cognitive impairment, Epileptic encephalopathy, early infantile AD 92 83
SCN9A Paroxysmal extreme pain disorder, Small fiber neuropathy, Erythermalgia, primary, Geberalized epilepsy with febrile seizures plus, type 7, Insensitivity to pain, congenital, autosomal recessive AD/AR 51 116
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 23 48
SERPINI1 Encephalopathy, familial, with neuroserpin inclusion bodies AD 5 8
SIK1 Epileptic encephalopathy, early infantile AD 5 6
SLC2A1 Stomatin-deficient cryohydrocytosis with neurologic defects, Epilepsy, idiopathic generalized, GLUT1 deficiency syndrome AD/AR 98 262
SLC6A1 Myoclonic-astastic epilepsy AD 33 18
SLC6A8* Creatine deficiency syndrome XL 32 128
SLC9A6 Mental retardation, syndromic, Christianson XL 24 21
SLC12A5 Epileptic encephalopathy, early infantile AR 4 14
SLC13A5 Epileptic encephalopathy, early infantile AR 16 19
SLC19A3 Thiamine metabolism dysfunction syndrome AR 25 37
SLC25A1 Combined D-2- and L-2-hydroxyglutaric aciduria AR 8 16
SLC25A15* Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome AR 22 36
SLC25A22 Epileptic encephalopathy, early infantile AR 7 10
SLC35A2 Congenital disorder of glycosylation XL 15 15
SLC39A8 Congenital disorder of glycosylation, type IIn AR 7 6
SLC46A1 Folate malabsorption AR 17 20
SMS Mental retardation, Snyder-Robinson XL 11 14
SNAP25 Myasthenic syndrome, congenital AD 2 3
SNORD118 Leukoencephalopathy, brain calcifications, and cysts (Labrune syndrome) AR 6 35
SOX10 Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease AD 41 136
SPATA5 Epilepsy, hearing loss, and mental retardation syndrome; EHLMRS AR 20 21
SPTAN1 Epileptic encephalopathy, early infantile AD 12 36
ST3GAL3 Epileptic encephalopathy, early infantile, Mental retardation AR 3 3
ST3GAL5 Ganglioside GM3 synthase deficiency AR 7 5
STX1B Generalized epilepsy with febrile seizures plus AD 10 9
STXBP1 Epileptic encephalopathy, early infantile AD 129 176
SUMF1 Multiple sulfatase deficiency AR 21 52
SUOX Sulfocysteinuria AR 6 28
SYN1 Epilepsy, with variable learning disabilities and behavior disorders XL 11 7
SYNGAP1 Mental retardation AD 82 69
SYNJ1 Epileptic encephalopathy, early infantile, 53, Parkinson disease 20, early-onset AR 8 23
SZT2 Epileptic encephalopathy, early infantile AR 9 19
TAF1 Dystonia 3, torsion, X-linked, Mental retardation, X-linked, syndromic 33 XL 12 14
TBC1D24 Deafness, Deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures (DOORS) syndrome, Deafness, autosomal dominant, 65, Myoclonic epilepsy, infantile, familial, Epileptic encephalopathy, early infantile, 16 AD/AR 41 51
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 11 7
TBCK Hypotonia, infantile, with psychomotor retardation and characteristic facies 3 AR 13 14
TBL1XR1* Mental retardation, autosomal dominant 41, Pierpont syndrome AD 21 18
TCF4 Corneal dystrophy, Fuchs endothelial, Pitt-Hopkins syndrome AD 86 141
TPP1 Spinocerebellar ataxia, Neuronal ceroid lipofuscinosis type 2 AR 56 110
TREX1 Vasculopathy, retinal, with cerebral leukodystrophy, Chilblain lupus, Aicardi-Goutières syndrome AD/AR 30 68
TSC1 Lymphangioleiomyomatosis, Tuberous sclerosis AD 138 346
TSC2 Lymphangioleiomyomatosis, Tuberous sclerosis AD 322 1137
TTC19 Mitochondrial complex III deficiency, nuclear type 2 AR 13 9
TUBB4A* Leukodystrophy, hypomyelinating, Dystonia AD 39 40
UBA5* Epileptic encephalopathy, early infantile, 44, Spinocerebellar ataxia, autosomal recessive 24 AR 16 14
UBE2A Mental retardation, syndromic, Nascimento XL 8 25
UBE3A* Angelman syndrome AD 165 193
UNC80 Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 AR 24 16
VPS13A Choreoacanthocytosis AR 19 113
WDR26 Skraban-Deardorff syndrome 12 33
WDR45 Neurodegeneration with brain iron accumulation XL 37 70
WWOX Epileptic encephalopathy, early infantile, Spinocerebellar ataxia AR 38 42
YY1 Gabriele-de Vries syndrome (GADEVS) AD 7 23
ZEB2* Mowat-Wilson syndrome AD 135 280
ZFYVE26 Spastic paraplegia 15 AR 26 38

* 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 the panel

Gene Genomic location HG19 HGVS RefSeq RS-number
ADSL Chr22:40742514 c.-49T>C NM_000026.2
ALDH3A2 Chr17:19561044 c.681-14T>A/G NM_001031806.1
ALDH7A1 Chr5:125907053 c.696-502G>C NM_001182.4
AMT Chr3:49459938 c.-55C>T NM_000481.3 rs386833677
ARG1 Chr6:131901748 c.306-611T>C NM_000045.3
ARSA Chr22:51064121 c.1108-12C>G NM_000487.5 rs757806374
BTD Chr3:15687154 c.*159G>A NM_000060.2 rs530872564
CACNA1A Chr19:13341036 c.5404-13G>A NM_001127221.1
CASR Chr3:121994640 c.1378-19A>C NM_001178065.1
CDKL5 ChrX:18525053 c.-162-2A>G NM_003159.2 rs786204973
CLN3 Chr16:28497984 c.461-13G>C NM_000086.2 rs386833721
COL4A1 Chr13:110802679 c.*31G>T NM_001845.4
COL4A1 Chr13:110802678 c.*32G>T NM_001845.4
COL4A1 Chr13:110802675 c.*35C>A NM_001845.4
D2HGDH Chr2:242680425 c.293-23A>G NM_152783.3
DARS2 Chr1:173797449 c.228-21_228-20insC NM_018122.4 rs367543010
EIF2B5 Chr3:183855941 c.685-13C>G NM_003907.2
ETFDH Chr4:159593534 c.-75A>G NM_004453.2
FGF12 Chr3:191857076 c.*4722T>C NM_021032.4
GABRA1 Chr5:161274418 c.-248+1G>T NM_000806.5
GABRB3 Chr15:27020313 c.-2204G>A NM_000814.5
GABRB3 Chr15:27020399 c.-2290T>C NM_000814.5 rs546389769
GALC Chr14:88459917 c.-74T>A NM_001201402.1
GAMT Chr19:1399508 c.391+15G>T NM_138924.2 rs367567416
GCDH Chr19:13010271 c.1244-11A>G NM_000159.3
GJC2 Chr1:228337561 c.-167A>G NM_020435.3
GJC2 Chr1:228337558 c.-170A>G NM_020435.3
GJC2 Chr1:228337709 c.-20+1G>C NM_020435.3
GRN Chr17:42422705 c.-8+3A>T NM_002087.2 rs63751020
GRN Chr17:42422707 c.-8+5G>C NM_002087.2 rs63750313
GRN Chr17:42422701 c.-9A>G NM_002087.2
L2HGDH Chr14:50735527 c.906+354G>A NM_024884.2
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
NDUFAF6 Chr8:96046914 c.298-768T>C NM_152416.3 rs575462405
NDUFS7 Chr19:1386643 c.17-1167C>G NM_024407.4
NUBPL Chr14:32319298 c.815-27T>C NM_025152.2 rs118161496
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
PLP1 ChrX:103042413 c.454-314T>A/G NM_000533.3
PLP1 ChrX:103042405 c.454-322G>A NM_000533.3
PNKP Chr19:50364799 c.1387-33_1386+49delCCTCCTCCCCTGACCCC NM_007254.3 rs752902474
POLR3A Chr10:79769277 c.1909+18G>A NM_007055.3 rs267608677
POLR3A Chr10:79769273 c.1909+22G>A NM_007055.3 rs191875469
POLR3B Chr12:106831447 c.1857-12A>G NM_018082.5 rs528038639
POLR3B Chr12:106804589 c.967-15A>G NM_018082.5
PPT1 Chr1:40539203 c.*526_*529delATCA NM_000310.3 rs386833624
PPT1 Chr1:40558194 c.125-15T>G NM_000310.3 rs386833629
PSAP Chr10:73583679 c.778-26C>A NM_001042465.1
PTS Chr11:112100215 c.164-716A>T NM_000317.2
PTS Chr11:112099026 c.84-291A>G NM_000317.2
PTS Chr11:112098994 c.84-323A>T NM_000317.2 rs794726657
QDPR Chr4:17500790 c.436+2552A>G NM_000320.2
RNASEH2B Chr13:51501530 c.65-13G>A NM_024570.3
SCN1A Chr2:166913031 c.384-21T>A NM_006920.4 rs373168416
SCN1A Chr2:166854699 c.4306-14T>G NM_006920.4
SCN1A Chr2:166848946 c.4820-14T>G NM_006920.4
SCN1A Chr2:166908215 c.964+14T>G NM_006920.4 rs794726837
SLC19A3 Chr2:228560811 c.980-14A>G NM_025243.3 rs200542114
SLC2A1 Chr1:43395462 c.680-11G>A NM_006516.2
SOX10 Chr22:38412215 c.-31954C>T NM_006941.3 rs606231342
SOX10 Chr22:38379877 c.-84-2A>T NM_006941.3
TBCD Chr17:80851411 c.1564-12C>G NM_005993.4
TPP1 Chr11:6637752 c.887-18A>G NM_000391.3
TSC2 Chr16:2098067 c.-30+1G>C NM_000548.3 rs587778004
TSC2 Chr16:2127477 c.2838-122G>A NM_000548.3
TSC2 Chr16:2138031 c.5069-18A>G NM_000548.3 rs45484794
TSC2 Chr16:2110656 c.976-15G>A NM_000548.3 rs45517150
ZEB2 Chr2:145274987 c.-69-1G>A NM_014795.3

Added and removed genes from the panel

Genes added Genes removed
ABAT
AIFM1
ALDH3A2
AP4B1
AP4E1
AP4M1
AP4S1
APOPT1
ASNS
ATP1A3
BRAT1
CC2D1A
CLCN4
COX6B1
CTC1
CYP27A1
D2HGDH
DARS
DDC
DHFR
DNM1L
DPYS
ECHS1
ECM1
ETHE1
FA2H
FAR1
FARS2
FGF12
GABRB2
GFM1
GLB1
GLRB
GNB1
GRIK2
GRIN1
GTPBP3
HACE1
HECW2
HIBCH
HTRA1
HTT
IBA57
KCNH1
LMNB1
LRPPRC
LYRM7
MAGI2
MRPL44
MTFMT
NACC1
NDUFAF6
NDUFS2
NDUFS4
NDUFS7
NDUFS8
NDUFV1
NFU1
NUBPL
PIGN
PIGO
PIGT
PIGV
PRIMA1
PYCR2
RARS
RMND1
RNF216
ROGDI
SCO1
SDHAF1
SERAC1
SLC25A1
SLC39A8
SNORD118
SPATA5
SYNJ1
TAF1
TBCD
TBCE
TBCK
TBL1XR1
TTC19
UBA5
UNC80
VPS13A
WDR26
YY1
ZFYVE26
PRICKLE2

Test strength

The strengths of this test include:
  • 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

Test limitations

This panel does not detect the expansion of a 12-nucleotide repeat (rs193922905) in the promoter region of *CSTB*. 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).

This test does not detect the following:
  • 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).

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

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 beyond paediatric epilepsy panel covers classical genes associated with epilepsy, metabolic epilepsy, sudden unexpected death, leukoencephalopathy and neuronal ceroid lipofuscinosis. 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%

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 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.

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 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 of sequence variants is confirmation of variants classified as pathogenic or likely pathogenic using bi-directional Sanger sequencing. Variant(s) fulfilling all of the following criteria are not Sanger confirmed: 1) the variant quality score is above the internal threshold for a true positive call, 2) an unambiguous IGV in-line with the variant call and 3) previous Sanger confirmation of the same variant at least three times at Blueprint Genetics. Reported variants of uncertain significance are confirmed with bi-directional Sanger sequencing only if the quality score is below our internally defined quality score for 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.

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. For eligible cases, Blueprint Genetics offers a no charge service to investigate the role of reported VUS (VUS Clarification Service).

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.