Beyond Paediatric Epilepsy Panel – for Europe and Middle East

Updated
Summary
  • Is a 379 gene panel that includes assessment of non-coding variants
  • 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 2019

Analysis methods
  • PLUS
Availability

4 weeks

Number of genes

379

Test code

NE2401

Panel size

Large

Summary

The Blueprint Genetics Beyond Paediatric Epilepsy Panel – for Europe and Middle East (test code NE2401):

ICD codes

Commonly used ICD-10 code(s) when ordering the Beyond Paediatric Epilepsy Panel – for Europe and Middle East

ICD-10 Disease
G40.9 Epilepsy
E75.4 Neuronal ceroid lipofuscinosis

Sample Requirements

  • 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.

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 – for Europe and Middle East and their clinical significance

Gene Associated phenotypes Inheritance ClinVar HGMD
ABAT GABA-transaminase deficiency AR 11 12
ABCA2 Intellectual disability and seizures AR 4
ABCD1* Adrenoleukodystrophy XL 95 663
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
AFG3L2* Spastic ataxia, Spinocerebellar ataxia AD/AR 22 40
AGA Aspartylglucosaminuria AR 48 37
AIFM1 Deafness, Combined oxidative phosphorylation deficiency 6, Cowchock syndrome XL 27 31
AIMP1 Leukodystrophy, hypomyelinating AR 4 5
ALDH3A2 Sjogren-Larsson syndrome AR 74 111
ALDH5A1 Succinic semialdehyde dehydrogenase deficiency AR 16 70
ALDH7A1 Epilepsy, pyridoxine-dependent AR 52 123
ALG13 Congenital disorder of glycosylation XL 5 12
ALKBH8 Intellectual disability AR
AMACR Alpha-methylacyl-CoA racemase deficiency, Bile acid synthesis defect AR 3 8
AMT Glycine encephalopathy AR 42 95
ANKRD11* KBG syndrome AD 142 132
AP2M1 Epilepitic encephalopathy AD
AP3B2 Epileptic encephalopathy, early infantile, 48 6 12
AP4B1 Spastic paraplegia 47, autosomal recessive AR 17 18
AP4E1 Stuttering, familial persistent, 1, Spastic paraplegia 51, autosomal recessive AR 7 15
AP4M1 Spastic paraplegia 50, autosomal recessive AR 16 13
AP4S1#* Spastic paraplegia 52, autosomal recessive AR 9 8
APOPT1 Mitochondrial complex IV deficiency AR 4 5
ARG1 Hyperargininemia AR 28 54
ARHGEF9 Epileptic encephalopathy, early infantile XL 10 23
ARID1B Coffin-Siris syndrome, Mental retardation AD 153 185
ARSA Metachromatic leukodystrophy AR 113 246
ARX# Lissencephaly, Epileptic encephalopathy, Corpus callosum, agenesis of, with abnormal genitalia, Partington syndrome, Proud syndrome, Hydranencephaly with abnormal genitalia, Mental retardation XL 66 93
ASAH1 Spinal muscular atrophy with progressive myoclonic epilepsy, Farber lipogranulomatosis AR 16 71
ASNS* Asparagine synthetase deficiency AR 21 26
ASPA Aspartoacylase deficiency (Canavan disease) AR 54 102
ASXL3 Bainbridge-Ropers syndrome AD 45 49
ATP13A2 Parkinson disease (Kufor-Rakeb syndrome) AR 21 40
ATP1A3 Alternating hemiplegia of childhood, Dystonia 12 AD 79 112
ATP6V1A Cutis laxa, autosomal recessive, type IID, Epileptic encephalopathy AD/AR 8 8
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 65 165
BRAT1 Rigidity and multifocal seizure syndrome, lethal neonatal AR 19 18
BTD Biotinidase deficiency AR 170 247
C12ORF57 Corpus callosum hypoplasia, recessive, Temtamy syndrome AR 7 6
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
CACNA1D Primary aldosteronism, seizures, and neurologic abnormalities, Sinoatrial node dysfunction and deafness AD/AR 7 8
CACNA1E Epileptic encephalopathy AD 8 6
CACNA1H Childhood absence epilepsy AD 9 55
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 87 112
CASR Hypocalcemia, Neonatal hyperparathyroidism, Familial Hypocalciuric hypercalcemia with transient Neonatal hyperparathyroidism AD/AR 104 396
CC2D1A Mental retardation, autosomal recessive 3 AR 3 7
CDK9 AR 1
CDKL5 Epileptic encephalopathy, early infantile, Rett syndrome, atypical, Angelman-like syndrome XL 312 331
CERS1# Epilepsy, progressive myoclonic AR 11 1
CHD2 Epileptic encephalopathy, childhood-onset AD 85 59
CHRNA2 Epilepsy, nocturnal frontal lobe AD 3 7
CHRNA4 Epilepsy, nocturnal frontal lobe AD 8 18
CHRNB2 Epilepsy, nocturnal frontal lobe AD 9 13
CLCN2 Leukoencephalopathy with ataxia, Epilepsy AD/AR 30 36
CLCN4 Mental retardation, X-linked 49 XL 21 17
CLN3 Neuronal ceroid lipofuscinosis, type 3 AR 100 72
CLN5 Neuronal ceroid lipofuscinosis, type 5 AR 62 47
CLN6 Neuronal ceroid lipofuscinosis, type 6 AR 41 83
CLN8 Neuronal ceroid lipofuscinosis, type 8 AR 45 44
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
COA7 Spinocerebellar ataxia, Charcot-Marie-Tooth disease AR 2 7
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 58 107
COL4A3BP Mental retardation, autosomal dominant 34 AD 6 7
COX15 Leigh syndrome, Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency AR 7 5
COX6B1 Mitochondrial complex IV deficiency AR 2 3
CPT2 Carnitine palmitoyltransferase II deficiency AR 72 111
CSF1R Leukoencephalopathy, diffuse hereditary, with spheroids AD 56 83
CSNK2B Intellectual disability and seizures AD 7 5
CSTB Epilepsy, progressive myoclonic AR 19 15
CTC1 Cerebroretinal microangiopathy with calcifications and cysts AR 21 33
CTSD Ceroid lipofuscinosis, neuronal AR 12 18
CTSF Neuronal ceroid lipofuscinosis AR 8 11
CUL4B Mental retardation, syndromic, Cabezas XL 23 38
CYFIP2 Early infantile epileptic encephalopathy, Epilepsy AD 2 3
CYP27A1 Cerebrotendinous xanthomatosis AR 69 110
D2HGDH D-2-hydroxyglutaric aciduria 1 AR 13 33
DARS Hypomyelination with brainstem and spinal cord involvement and leg spasticity AR 11 17
DARS2 Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation AR 27 61
DCX Lissencephaly, Subcortical laminal heterotopia XL 131 142
DDC Aromatic l-amino acid decarboxylase deficiency AR 14 51
DDX3X Mental retardation, X-linked 102 XL 84 51
DEGS1# Leukodystrophy, hypomyelinating AR
DENND5A Epileptic encephalopathy, early infantile, 49 AR 6 6
DEPDC5 Epilepsy, familial focal, with variable foci AD 87 78
DHFR* Megaloblastic anemia due to dihydrofolate reductase deficiency AR 2 5
DHPS# AR
DNAJC5 Kufs disease,, Ceroid lipofuscinosis, neuronal 4, Parry AD 2 2
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
DPYD 5-fluorouracil toxicity, Schizophrenia AD/AR 62 86
DPYS Dihydropyriminidase deficiency AR 8 29
DYRK1A Mental retardation AD 94 77
EARS2 Combined oxidative phosphorylation deficiency AR 14 30
ECHS1 Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency AR 23 33
ECM1 Lipoid proteinosis AR 13 61
EEF1A2 Epileptic encephalopathy, early infantile, Mental retardation AD 17 12
EFHC1 Epilepsy, myoclonic juvenile, Epilepsy, severe intractable, Epilepsy, juvenile absence AD/AR 5 38
EIF2B1 Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy AR 7 9
EIF2B2 Leukoencephalopathy with vanishing white matter, Ovarioleukodystrophy AR 12 28
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 20 98
EIF3F Intellectual disability AR
EPM2A Epilepsy, progressive myoclonic AR 17 77
EPRS Leukodystrophy, hypomyelinating AR 6 6
ETFA Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 8 29
ETFB Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 6 15
ETFDH Glutaric aciduria, Multiple acyl-CoA dehydrogenase deficiency AR 43 190
ETHE1 Ethylmalonic encephalopathy AR 38 36
FA2H Spastic paraplegia AR 18 51
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 17 20
FDFT1 Growth retardation, developmental delay, and facial dysmorphism 3 5
FDX1L Myopathy AR 1 2
FGF12 Epileptic encephalopathy, early infantile, 47 AD 6 10
FH Hereditary leiomyomatosis and renal cell cancer AD/AR 178 207
FLNA Frontometaphyseal dysplasia, Osteodysplasty Melnick-Needles, Otopalatodigital syndrome type 1, Otopalatodigital syndrome type 2, Terminal osseous dysplasia with pigmentary defects XL 133 257
FOLR1 Cerebral folate deficiency AR 10 28
FOXG1 Rett syndrome, congenital variant AD 106 156
FOXRED1 Leigh syndrome, Mitochondrial complex I deficiency AR 15 8
FRRS1L Epileptic encephalopathy, early infantile, 37 AR 9 6
FUT8 Congenital disorder of glycosylation AR 4 4
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
GALC Krabbe disease AR 107 243
GAMT Guanidinoacetate methyltransferase deficiency AR 18 58
GCDH Glutaric aciduria AR 90 241
GCH1 Dopa-Responsive Dystonia Hyperphenylalaninemia, BH4-deficient, GTP Cyclohydrolase 1-Deficient Dopa-Responsive Dystonia AD/AR 48 240
GFAP Alexander disease AD 114 131
GFM1 Combined oxidative phosphorylation deficiency AR 19 19
GFM2 Combined oxidative phosphorylation deficiency AR 5 6
GJC2 Spastic paraplegia, Lymphedema, hereditary, Leukodystrophy, hypomyelinating AD/AR 26 57
GLB1 GM1-gangliosidosis, Mucopolysaccharidosis (Morquio syndrome) AR 90 220
GLDC Glycine encephalopathy AR 139 425
GLRB Hyperekplexia 2 AR 6 18
GNAO1 Epileptic encephalopathy, early infantile, Epileptic encephalopathy, early infantile, 17 AD 26 35
GNB1 Mental retardation, autosomal dominant 42 AD 15 24
GNE Inclusion body myopathy, Nonaka myopathy, Sialuria AD/AR 78 214
GOLGA2 Microcephaly, seizures, and developmental delay AR 2
GOSR2* Epilepsy, progessive myoclonic AR 6 4
GPAA1 Cerebellar atrophy, developmental delay, and seizures (CADEDS) AR 7 9
GPHN Hyperekplexia, Molybdenum cofactor deficiency AD/AR 35 20
GRIA3 Mental retardation XL 12 23
GRIA4 Intellectual disability and seizures 5 5
GRIK2 Mental retardation, autosomal recessive 6 AR 2 7
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
GRN Frontotemporal lobar degeneration with TDP43 inclusions, GRN-related, Neuronal ceroid lipofuscinosis AD/AR 43 214
GTPBP3 Combined oxidative phosphorylation deficiency 23 AR 14 15
HACE1 Spastic paraplegia and psychomotor retardation with or without seizures AR 13 13
HCN1 Epileptic encephalopathy, early infantile AD 13 14
HCN2#* Epilepsy AD/AR 1 8
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
HSD17B10 17-beta-hydroxysteroid dehydrogenase X deficiency, Mental retardation, syndromic XL 10 15
HSPD1* Spastic paraplegia, Leukodystrophy, hypomyelinating AD/AR 5 5
HTRA1 Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy type 2 (CADASIL2), Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) AD/AR 25 46
HTT Huntington disease, Lopes-Maciel-Rodan syndrome (LOMARS) AD/AR 8 7
IBA57 Multiple mitochondrial dysfunctions syndrome 3, Spastic paraplegia 74, autosomal recessive AR 14 23
ICK Endocrine-cerebroosteodysplasia, Epilepsy, juvenile myoclonic AD/AR 1 3
IQSEC2 Mental retardation XL 55 56
IRF2BPL Neurodevelopmental disorder with hypotonia, seizures, and absent language AD 9 2
KCNA1 Episodic ataxia/myokymia syndrome AD 24 45
KCNA2 Epileptic encephalopathy, early infantile AD 15 21
KCNB1 Early infantile epileptic encephalopathy AD 27 30
KCNC1 Epilepsy, progressive myoclonic AD 5 3
KCNH1 Temple-Baraitser syndrome, Zimmermann-Laband syndrome 1 AD/AR 16 13
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
KCTD7 Epilepsy, progressive myoclonic AR 18 20
KDM5C Mental retardation, syndromic, Claes-Jensen XL 47 55
KIAA2022 Mental retardation XL 42 40
KIF1A Spastic paraplegia, Neuropathy, hereditary sensory, Mental retardation AD/AR 63 42
KMT2E 4
L2HGDH L-2-hydroxyglutaric aciduria AR 15 79
LGI1 Epilepsy, familial temporal lobe AD 28 54
LMNB1 Leukodystrophy, demyelinating, adult-onset, autosomal dominant AD 2 35
LRPPRC Leigh syndrome, French-Canadian type AR 55 17
LYRM7 Mitochondrial complex III deficiency, nuclear type 8 AR 5 9
MACF1 Lissencephaly AD 1 9
MAGI2 Nephrotic syndrome 15 AR 7 27
MARS2 Combined oxidative phosphorylation deficiency AR 8 5
MBD5 Mental retardation AD 62 90
MBOAT7 Mental retardation, autosomal recessive 57 AR 5 5
MDH2 Epileptic encephalopathy, early infantile, 51 AR 5 9
MECP2 Angelman-like syndrome, Autism, Rett syndrome, Encephalopathy, Mental retardation XL 506 1039
MED12 Ohdo syndrome, Mental retardation, with Marfanoid habitus, FG syndrome, Opitz-Kaveggia syndrome, Lujan-Fryns syndrome XL 29 30
MED17 Microcephaly, postnatal progressive, with seizures and brain atrophy AR 4 4
MEF2C Mental retardation AD 45 84
MFSD8 Ceroid lipofuscinosis, neuronal AR 27 47
MIPEP* Combined oxidative phosphorylation deficiency 31 AR 5 8
MLC1 Megalencephalic leukoencephalopathy with subcortical cysts AR 39 108
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 65 122
MTOR Smith-Kingsmore syndrome AD 26 24
NACC1 Neurodevelopmental disorder with epilepsy, cataracts, feeding difficulties, and delayed brain myelination (NECFM) AD 2 3
NBEA* Epilepsy AD 3 13
NDST1 Mental retardation, autosomal recessive 46 AR 4 7
NDUFAF3 Mitochondrial complex I deficiency AR 6 9
NDUFAF5 Mitochondrial complex I deficiency AR 8 12
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
NEU1 Sialidosis AR 22 62
NEUROD2 Epileptic encephalopathy AD
NFU1 Multiple mitochondrial dysfunctions syndrome 1 AR 6 15
NHLRC1 Epilepsy, progressive myoclonic AR 14 70
NKX6-2 Spastic ataxia 8, autosomal recessive, with hypomyelinating leukodystrophy AR 4 8
NOTCH3 Cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), Lateral meningocele syndrome AD 87 364
NPRL3 Epilepsy, familial focal, with variable foci 3 AD 21 10
NRXN1 Pitt-Hopkins like syndrome, Schizophrenia AD/AR 99 311
NT5C2 Spastic paraplegia 45 AR 8 7
NUBPL Mitochondrial complex I deficiency AR 9 10
NUS1* Congenital disorder of glycosylation, type 1aa 4 5
OFD1 Simpson-Golabi-Behmel syndrome, Retinitis pigmentosa, Orofaciodigital syndrome, Joubert syndrome XL 153 160
OPHN1 Mental retardation, with cerebellar hypoplasia and distinctive facial appearance XL 28 42
P4HTM Intellectual disability and seizures AR
PARS2 Alpers syndrome AR 3 6
PCDH19 Epileptic encephalopathy, early infantile XL 116 200
PGK1 Phosphoglycerate kinase 1 deficiency XL 16 26
PHACTR1 Epileptic encephalopathy AD 4 2
PHF6 Borjeson-Forssman-Lehmann syndrome XL 22 29
PIGA* Multiple congenital anomalies-hypotonia-seizures syndrome XL 24 27
PIGB Epileptic encephalopathy AR
PIGC* AR 4 4
PIGG Mental retardation, autosomal recessive 53 AR 7 6
PIGN* Multiple congenital anomalies-hypotonia-seizures syndrome 1 AR 33 34
PIGO Hyperphosphatasia with mental retardation syndrome 2 AR 18 20
PIGP Epileptic encephalopathy, early infantile, 55 AR 2
PIGQ Epileptic encephalopathy AR 3 4
PIGS Epileptic encephalopathy AR
PIGT Multiple congenital anomalies-hypotonia-seizures syndrome 3 AR 13 12
PIGV Hyperphosphatasia with mental retardation syndrome 1 AR 9 16
PIGW Hyperphosphatasia with mental retardation syndrome 5 AR 6 4
PITRM1 AR 2
PLAA Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA) 3 3
PLCB1 Epileptic encephalopathy, early infantile AR 8 10
PLP1 Spastic paraplegia, Pelizaeus-Merzbacher disease XL 60 348
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
POLR3A Leukodystrophy, hypomyelinating AR 29 91
POLR3B Leukodystrophy, hypomyelinating AR 19 58
PPP2CA AD 2
PPP3CA Epilepitic encephalopathy AD 8 11
PPT1 Ceroid lipofuscinosis, neuronal AR 94 77
PRICKLE1 Epilepsy, progressive myoclonic AD/AR 3 16
PRIMA1 Epilepsy, nocturnal frontal lobe AR 1
PRODH* Hyperprolinemia AR 52 10
PROSC Epilepsy AR 7 12
PRRT2 Episodic kinesigenic dyskinesia, Seizures, benign familial infantile, 2, Convulsions, familial infantile, with paroxysmal choreoathetosis AD 42 99
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
PTPN23 Epileptic encephalopathy AR 1 4
PTS Hyperphenylalaninemia, BH4-deficient AR 34 112
PUM1 Ataxia AD 3 11
PURA Mental retardation AD 74 47
PYCR2 Leukodystrophy, hypomyelinating 10 AR 11 13
QARS Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy AR 14 10
QDPR Hyperphenylalaninemia, BH4-deficient AR 14 66
RAB39B Waisman parkinsonism-mental retardation syndrome, Mental retardation XL 6 17
RALA* Intellectual disability AD 1
RARS Leukodystrophy, hypomyelinating 9 AR 12 11
RELN Lissencephaly, Epilepsy, familial temporal lobe AD/AR 25 44
RMND1* Combined oxidative phosphorylation deficiency AR 17 15
RNASEH2A Aicardi-Goutières syndrome AR 13 21
RNASEH2B Aicardi-Goutières syndrome AR 16 41
RNASEH2C Aicardi-Goutières syndrome AR 6 14
RNASET2 Leukoencephalopathy, cystic, without megalencephaly AR 8 12
RNF216* Cerebellar ataxia and hypogonadotropic hypogonadism (Gordon Holmes syndrome) AR 10 14
ROGDI Kohlschutter-Tonz syndrome AR 14 13
RORB Epilepsy AD 3 9
SAMHD1 Aicardi-Goutières syndrome, Chilblain lupus 2 AD/AR 25 56
SCARB2 Epilepsy, progressive myoclonic AR 23 27
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
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 61 125
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
SERPINI1 Encephalopathy, familial, with neuroserpin inclusion bodies AD 5 9
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
SLC1A4 Spastic tetraplegia, thin corpus callosum, and progressive microcephaly AR 4 8
SLC25A1 Combined D-2- and L-2-hydroxyglutaric aciduria AR 8 24
SLC25A15* Hyperornithinemia-hyperammonemia-homocitrullinemia syndrome AR 24 36
SLC25A22 Epileptic encephalopathy, early infantile AR 8 10
SLC25A42 AR 1 1
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
SLC39A8# Congenital disorder of glycosylation, type IIn AR 7 6
SLC46A1 Folate malabsorption AR 17 23
SLC6A1 Myoclonic-astastic epilepsy AD 38 41
SLC6A8* Creatine deficiency syndrome XL 38 133
SLC9A6 Mental retardation, syndromic, Christianson XL 24 28
SMARCA2 Nicolaides-Baraitser syndrome AD 41 73
SMC1A Cornelia de Lange syndrome XL 73 87
SMS Mental retardation, Snyder-Robinson XL 11 14
SNAP25 Myasthenic syndrome, congenital AD 2 4
SNORD118 Leukoencephalopathy, brain calcifications, and cysts (Labrune syndrome) AR 6 39
SOX10 Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease, Kallmann syndrome AD 56 148
SPATA5 Schizophrenia, Epilepsy, hearing loss, and mental retardation syndrome (EHLMRS) AR 27 27
SPTAN1 Epileptic encephalopathy, early infantile AD 16 40
SPTBN4 Myopathy, congenital, with neuropathy and deafness AR 6 7
ST3GAL3 Epileptic encephalopathy, early infantile, Mental retardation AR 3 5
ST3GAL5 Ganglioside GM3 synthase deficiency AR 10 5
STX1B Generalized epilepsy with febrile seizures plus AD 11 9
STXBP1 Epileptic encephalopathy, early infantile AD 140 190
SUMF1 Multiple sulfatase deficiency AR 21 53
SUOX Sulfocysteinuria AR 8 29
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
TAF1 Dystonia 3, torsion, X-linked, Mental retardation, X-linked, syndromic 33 XL 13 14
TBC1D20 Warburg micro syndrome 4 AR 6 6
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
TBL1XR1* Mental retardation, autosomal dominant 41, Pierpont syndrome AD 25 23
TCF4 Corneal dystrophy, Fuchs endothelial, Pitt-Hopkins syndrome AD 105 146
TPK1 Thiamine metabolism dysfunction syndrome 5 AR 14 11
TPP1 Spinocerebellar ataxia, Neuronal ceroid lipofuscinosis type 2 AR 75 112
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
TUBB4A* Leukodystrophy, hypomyelinating, Dystonia AD 39 42
UBA5* Epileptic encephalopathy, early infantile, 44, Spinocerebellar ataxia, autosomal recessive 24 AR 16 15
UBE2A Mental retardation, syndromic, Nascimento XL 9 25
UBE3A* Angelman syndrome AD 176 202
UNC80 Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 AR 26 20
VAMP2 AD
VARS Early-onset progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT), Encephalopathy, progressive AR 12 6
VPS13A Choreoacanthocytosis AR 19 115
WARS2 Encephalopathy, mitochondrial AR 6 14
WASF1 Intellectual disability and seizures AD 3 3
WDR26 Skraban-Deardorff syndrome AD 13 34
WDR45 Neurodegeneration with brain iron accumulation XL 46 78
WWOX Epileptic encephalopathy, early infantile, Spinocerebellar ataxia AR 43 45
YY1 Gabriele-de Vries syndrome (GADEVS) AD 8 23
ZEB2* Mowat-Wilson syndrome AD 154 287
ZFYVE26 Spastic paraplegia 15 AR 63 39

* 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), 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 Beyond Paediatric Epilepsy Panel – for Europe and Middle East

Gene Genomic location HG19 HGVS RefSeq RS-number
ADSL Chr22:40742514 c.-49T>C NM_000026.2
AIFM1 ChrX:129274636 c.697-44T>G NM_004208.3
ALDH3A2 Chr17:19561044 c.681-14T>A/G NM_001031806.1
ALDH3A2 Chr17:19561044 c.681-14T>A NM_001031806.1
ALDH3A2 Chr17:19561044 c.681-14T>G NM_001031806.1
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
ARSA Chr22:51064129 c.1108-20A>G NM_000487.5
BTD Chr3:15683399 c.310-15delT NM_000060.2 rs587783008
BTD Chr3:15687154 c.*159G>A NM_000060.2 rs530872564
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
CASR Chr3:121994640 c.1378-19A>C NM_001178065.1
CDKL5 ChrX:18525053 c.-162-2A>G NM_003159.2 rs786204973
CLN3 Chr16:28493392 c.1056+34C>A NM_000086.2
CLN3 Chr16:28497984 c.461-13G>C NM_000086.2 rs386833721
CLN6 Chr15:68506515 c.297+113G>C NM_017882.2
COL4A1 Chr13:110802675 c.*35C>A NM_001845.4
COL4A1 Chr13:110802678 c.*32G>A/T NM_001845.4
COL4A1 Chr13:110802679 c.*31G>T NM_001845.4
CSF1R Chr5:149440654 c.1859-119G>A NM_005211.3
D2HGDH Chr2:242680425 c.293-23A>G NM_152783.3
DARS2 Chr1:173797449 c.228-22T>C NM_018122.4
DARS2 Chr1:173797449 c.228-22T>A NM_018122.4
DARS2 Chr1:173797450 c.228-21_228-20delTTinsC NM_018122.4
DARS2 Chr1:173797450 c.228-21_228-20delTTinsCC NM_018122.4
DARS2 Chr1:173797455 c.228-16C>A NM_018122.4
DARS2 Chr1:173797455 c.228-16C>G NM_018122.4
DARS2 Chr1:173797456 c.228-15C>G NM_018122.4
DARS2 Chr1:173797456 c.228-15C>A NM_018122.4
DARS2 Chr1:173797459 c.228-12C>A NM_018122.4
DARS2 Chr1:173797460 c.228-11C>G NM_018122.4
DEPDC5 Chr22:32150851 c.-57G>C NM_001242896.1
EFHC1 Chr6:52284844 NM_018100.3 rs559477321
EIF2B5 Chr3:183855941 c.685-13C>G NM_003907.2
ETFDH Chr4:159593534 c.-75A>G NM_004453.2
ETFDH Chr4:159602711 c.176-636C>G NM_004453.2
ETHE1 Chr19:44031407 NM_014297.3
FDFT1 Chr8:11660094 NM_004462.3
FDFT1 Chr8:11689003 c.880-24_880-23delTCinsAG NM_004462.3
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 NM_000814.5
GABRB3 Chr15:27020313 c.-2204G>A NM_000814.5
GABRB3 Chr15:27020399 c.-2290T>C NM_000814.5 rs546389769
GALC Chr14:88401064 c.*12G>A NM_000153.3 rs372641636
GALC Chr14:88459574 c.-66G>C NM_000153.3 rs146439771
GALC Chr14:88459575 c.-67T>G NM_000153.3 rs571945132
GALC Chr14:88459917 c.-74T>A NM_001201402.1
GALC Chr14:88459971 c.-128C>T NM_001201402.1 rs181956126
GAMT Chr19:1399508 c.391+15G>T NM_138924.2 rs367567416
GCDH Chr19:13010271 c.1244-11A>G NM_000159.3
GCH1 Chr14:55369403 c.-22C>T NM_000161.2
GJC2 Chr1:228337558 c.-170A>G NM_020435.3
GJC2 Chr1:228337561 c.-167A>G NM_020435.3
GJC2 Chr1:228337709 c.-20+1G>C NM_020435.3
GRN Chr17:42422701 c.-9A>G NM_002087.2
GRN Chr17:42422705 c.-8+3A>T NM_002087.2 rs63751020
GRN Chr17:42422705 c.-8+3A>G NM_002087.2
GRN Chr17:42422707 c.-8+5G>C NM_002087.2 rs63750313
L2HGDH Chr14:50735527 c.906+354G>A NM_024884.2
MEF2C Chr5:88179125 c.-510_-497delTCTTCCTCCTCCTC NM_002397.4
MLC1 Chr22:50502853 c.895-226T>G NM_015166.3
MLC1 Chr22:50523373 c.-42C>T NM_015166.3 rs771159578
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
NDUFAF5 Chr20:13767051 c.223-907A>C NM_024120.4
NDUFAF6 Chr8:96046914 c.298-768T>C NM_152416.3 rs575462405
NDUFAF6 Chr8:96048588 c.420+784C>T NM_152416.3 rs749738738
NOTCH3 Chr19:15303132 c.341-26_341-24delAAC NM_000435.2
OFD1 ChrX:13768358 c.935+706A>G NM_003611.2 rs730880283
OFD1 ChrX:13773245 c.1130-22_1130-19delAATT NM_003611.2 rs312262865
OFD1 ChrX:13773249 c.1130-20_1130-16delTTGGT NM_003611.2
PGK1 ChrX:77381262 c.1214-25T>G NM_000291.3
PLP1 ChrX:103031997 c.4+78_4+85delGGGGGTTC NM_000533.3
PLP1 ChrX:103041680 c.453+28_453+46delTAACAAGGGGTGGGGGAAA NM_000533.3
PLP1 ChrX:103042405 c.454-322G>A NM_000533.3
PLP1 ChrX:103042413 c.454-314T>A/G NM_000533.3
PLP1 ChrX:103042413 c.454-314T>A NM_000533.3
PLP1 ChrX:103042413 c.454-314T>G NM_000533.3
PNKP Chr19:50364799 c.1387-33_1386+49delCCTCCTCCCCTGACCCC NM_007254.3 rs752902474
POLR3A Chr10:79737218 c.*18C>T NM_007055.3
POLR3A Chr10:79743781 c.3337-11T>C NM_007055.3
POLR3A Chr10:79769273 c.1909+22G>A NM_007055.3 rs191875469
POLR3A Chr10:79769277 c.1909+18G>A NM_007055.3 rs267608677
POLR3B Chr12:106804589 c.967-15A>G NM_018082.5
POLR3B Chr12:106831447 c.1857-12A>G NM_018082.5 rs528038639
PPT1 Chr1:40539203 c.*526_*529delATCA NM_000310.3 rs386833624
PPT1 Chr1:40558194 c.125-15T>G NM_000310.3 rs386833629
PRRT2 Chr16:29825620 c.*345G>A NM_001256443.1
PSAP Chr10:73583679 c.778-26C>A NM_001042465.1
PTS Chr11:112098994 c.84-323A>T NM_000317.2 rs794726657
PTS Chr11:112099026 c.84-291A>G NM_000317.2
PTS Chr11:112100215 c.164-716A>T NM_000317.2
PTS Chr11:112101310 c.187-38dupG NM_000317.2
QDPR Chr4:17500790 c.436+2552A>G NM_000320.2
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
SNORD118 Chr17:8076761 NR_033294.1 rs116395281
SNORD118 Chr17:8076761 NR_033294.1
SNORD118 Chr17:8076762 NR_033294.1 rs201787275
SOX10 Chr22:38379877 c.-84-2A>T NM_006941.3
SOX10 Chr22:38412215 c.-31954C>T NM_006941.3 rs606231342
SOX10 Chr22:38412781 c.-32520C>G NM_006941.3
SPTAN1 Chr9:131390187 c.6690-17G>A NM_001130438.2 rs796053325
TAF1 ChrX:70749635 rs397509359
TBCD Chr17:80851411 c.1564-12C>G NM_005993.4
TPP1 Chr11:6637752 c.887-18A>G NM_000391.3
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
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
ABCA2
ACTL6B
ADAM22
ADPRHL2
ALKBH8
ANKRD11
AP2M1
AP3B2
ARID1B
ASXL3
ATP6V1A
C12ORF57
CACNA1B
CACNA1D
CACNA1E
CDK9
CLTC
CNKSR2
CNPY3
COA7
COL4A3BP
CSNK2B
CYFIP2
DDX3X
DEGS1
DENND5A
DHPS
DYRK1A
EIF3F
EPRS
FDFT1
FDX1L
FRRS1L
FUT8
GABBR2
GFM2
GOLGA2
GPAA1
GRIA4
HCN2
ICK
IRF2BPL
KCNMA1
KCNQ5
KCNT2
KCTD3
KIAA2022
KMT2E
MACF1
MBOAT7
MDH2
MED17
MIPEP
NBEA
NDST1
NDUFAF3
NDUFS6
NEUROD2
NKX6-2
NPRL3
NT5C2
NUS1
P4HTM
PARS2
PHACTR1
PIGB
PIGC
PIGG
PIGP
PIGQ
PIGS
PIGW
PITRM1
PLAA
PPP2CA
PPP3CA
PROSC
PTPN23
PUM1
QARS
RALA
RORB
SCN3A
SLC1A4
SLC25A42
SMARCA2
SMC1A
SPTBN4
TBC1D20
TPK1
TRAK1
TRIM8
VAMP2
VARS
WARS2
WASF1

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
  • 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

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: AP4S1 (NM_001254727:6), DEGS1 (NM_001321541:3), DHPS (NM_001206974:1), GABRG2 (NM_198903:6), SLC39A8 (NM_001135148:1). 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 (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 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%

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. 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 <20X sequencing depth 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 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 heterozygous and homo/hemizygous copy number variations with a size <10 and <3 target exons are confirmed by orthogonal methods such as qPCR if the specific CNV has been seen and confirmed 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, 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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