Whole exome sequencing Gene package Epilepsy version 2,

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1 Whole Exome Sequencing Gene package Epilepsy, version 2, Technical information After DNA was enriched using Agilent Sureselect Clinical Research Exome (CRE) Capture, samples were run on the Illumina Hiseq platform. The aim is to obtain 50 million total reads per exome with a mapped fraction >0.98. The average coverage of the exome is ~50x. Data are demultiplexed by Illumina software bcl2fastq. Reads are mapped to the genome using BWA (reference: bwa.sourceforge.net/). Variant detection is performed by Genome Analysis Toolkit (reference: Analysis is performed in Cartagenia using The Variant Calling File (VCF) followed by filtering. It is not excluded that pathogenic mutations are being missed using this technology. At this moment, there is not enough information about the sensitivity of this technique with respect to the detection of deletions and duplications of more than 5 nucleotides and of somatic mosaic mutations (all types of sequence changes). HGNC approved AARS Charcot Marie Tooth disease, axonal, type 2N, Epileptic encephalopathy, early infantile, 29, ABAT GABA transaminase deficiency, ABCC8 Diabetes mellitus, noninsulin dependent, Diabetes mellitus, permanent neonatal, Diabetes mellitus, transient neonatal 2, Hyperinsulinemic hypoglycemia, familial, 1, Hypoglycemia of infancy, leucine sensitive, ACTB Baraitser Winter syndrome 1, ?Dystonia, juvenile onset, ACY1 Aminoacylase 1 deficiency, ADSL Adenylosuccinase deficiency, ALDH7A1 Epilepsy, pyridoxine dependent, ALG1 Congenital disorder of glycosylation, type Ik, ALG11 Congenital disorder of glycosylation, type Ip, ALG13?Congenital disorder of glycosylation, type Is, Epileptic encephalopathy, early infantile, 36, ALG3 Congenital disorder of glycosylation, type Id, ALG6 Congenital disorder of glycosylation, type Ic, AMACR Alpha methylacyl CoA racemase deficiency, Bile acid synthesis defect, congenital, 4,

2 AMT Glycine encephalopathy, APOPT1 Mitochondrial complex IV deficiency, ARHGEF9 Epileptic encephalopathy, early infantile, 8, ARID1B Coffin Siris syndrome 1, ARX Epileptic encephalopathy, early infantile, 1, Hydranencephaly with abnormal genitalia, Lissencephaly 2, Mental retardation 29 and others, Partington syndrome, Proud syndrome, ASAH1 Farber lipogranulomatosis, Spinal muscular atrophy with progressive myoclonic epilepsy, ASL Argininosuccinic aciduria, ATP1A2 Alternating hemiplegia of childhood, Migraine, familial basilar, Migraine, familial hemiplegic, 2, ATP1A3 Alternating hemiplegia of childhood 2, CAPOS syndrome, Dystonia 12, ATP6AP2 Mental retardation, syndromic, Hedera type, ?Parkinsonism with spasticity, ATP7A Menkes disease, Occipital horn syndrome, Spinal muscular atrophy, distal 3, ATRX Alpha thalassemia myelodysplasia syndrome, somatic, Alpha thalassemia/mental retardation syndrome, Mental retardation hypotonic facies syndrome, AUTS2 Mental retardation 26, BOLA3 Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemia, BRAT1 Rigidity and multifocal seizure syndrome, lethal neonatal, BTD Biotinidase deficiency, CACNA1A Epileptic encephalopathy, early infantile, 42, Episodic ataxia, type 2, Migraine, familial hemiplegic, 1, Migraine, familial hemiplegic, 1, with progressive cerebellar ataxia, Spinocerebellar ataxia 6, CACNA1E No phenotype CACNA2D2 No phenotype

3 CASK FG syndrome 4, Mental retardation and microcephaly with pontine and cerebellar hypoplasia, Mental retardation, with or without nystagmus, CDKL5 Epileptic encephalopathy, early infantile, 2, CHD2 Epileptic encephalopathy, childhood onset, CHRNA2 Epilepsy, nocturnal frontal lobe, type 4, CHRNA4 Epilepsy, nocturnal frontal lobe, 1, {Nicotine addiction, susceptibility to}, CHRNB2 Epilepsy, nocturnal frontal lobe, 3, CLDN16 Hypomagnesemia 3, renal, CLDN19 Hypomagnesemia 5, renal, with ocular involvement, CLN3 Ceroid lipofuscinosis, neuronal, 3, CLN5 Ceroid lipofuscinosis, neuronal, 5, CLN6 Ceroid lipofuscinosis, neuronal, 6, Ceroid lipofuscinosis, neuronal, Kufs type, adult onset, CLN8 Ceroid lipofuscinosis, neuronal, 8, Ceroid lipofuscinosis, neuronal, 8, Northern epilepsy variant, CNNM2 Hypomagnesemia 6, renal, Hypomagnesemia, seizures, and mental retardation, CNTN2?Epilepsy, myoclonic, familial adult, 5, CNTNAP2 {Autism susceptibility 15}, Cortical dysplasia focal epilepsy syndrome, Pitt Hopkins like syndrome 1, COL4A1 Angiopathy, hereditary, with nephropathy, aneurysms, and muscle cramps, Brain small vessel disease with or without ocular anomalies, {Hemorrhage, intracerebral, susceptibility to}, Porencephaly 1, ?Retinal arteries, tortuosity of, COL4A3BP Mental retardation 34, COQ2 Coenzyme Q10 deficiency, primary, 1, {Multiple system atrophy, susceptibility to}, COQ4 Coenzyme Q10 deficiency, primary, 4, COQ8A Coenzyme Q10 deficiency, primary, 7, CPA6 Epilepsy, familial temporal lobe, 5, Febrile seizures, familial, 11, CPS1 Carbamoylphosphate synthetase I deficiency, {Pulmonary hypertension, neonatal, susceptibility to}, {Venoocclusive disease after bone marrow transplantation}

4 CPT2 CPT II deficiency, infantile, CPT II deficiency, lethal neonatal, CPT II deficiency, myopathic, stress induced, {Encephalopathy, acute, infection induced, 4, susceptibility to}, CSTB Epilepsy, progressive myoclonic 1A (Unverricht and Lundborg), CTSD Ceroid lipofuscinosis, neuronal, 10, CTSF Ceroid lipofuscinosis, neuronal, 13, Kufs type, CUL4B Mental retardation, syndromic 15 (Cabezas type), D2HGDH D 2 hydroxyglutaric aciduria, DCX Lissencephaly, Subcortical laminal heteropia, DEPDC5 Epilepsy, familial focal, with variable foci 1, DLAT Pyruvate dehydrogenase E2 deficiency, DNAJC5 Ceroid lipofuscinosis, neuronal, 4, Parry type, DNM1 Epileptic encephalopathy, early infantile, 31, DOCK7 Epileptic encephalopathy, early infantile, 23, DPAGT1 Congenital disorder of glycosylation, type Ij, Myasthenic syndrome, congenital, 13, with tubular aggregates, DPM1 Congenital disorder of glycosylation, type Ie, DPM2 Congenital disorder of glycosylation, type Iu, DPYD Dihydropyrimidine dehydrogenase deficiency, fluorouracil toxicity, DYNC1H1 Charcot Marie Tooth disease, axonal, type 20, Mental retardation 13, Spinal muscular atrophy, lower extremity predominant 1, AD, DYRK1A Mental retardation 7, EEF1A2 Epileptic encephalopathy, early infantile, 33, Mental retardation 38, EGF Hypomagnesemia 4, renal, EHMT1 Kleefstra syndrome, EPM2A Epilepsy, progressive myoclonic 2A (Lafora), FA2H Spastic paraplegia 35, FARS2 Combined oxidative phosphorylation deficiency 14, ?Spastic paraplegia 77, FASN No phenotype FGD1 Aarskog Scott syndrome, Mental retardation syndromic 16,

5 FLNA Cardiac valvular dysplasia, Congenital short bowel syndrome, FG syndrome 2, Frontometaphyseal dysplasia 1, Heterotopia, periventricular, Intestinal pseudoobstruction, neuronal, Melnick Needles syndrome, Otopalatodigital syndrome, type I, Otopalatodigital syndrome, type II, Terminal osseous dysplasia, FOLR1 Neurodegeneration due to cerebral folate transport deficiency, FOXG1 Rett syndrome, congenital variant, FOXRED1 Leigh syndrome due to mitochondrial complex I deficiency, Mitochondrial complex I deficiency, FXYD2 Hypomagnesemia 2, renal, GABRA1 {Epilepsy, childhood absence, susceptibility to, 4}, {Epilepsy, juvenile myoclonic, susceptibility to, 5}, Epileptic encephalopathy, early infantile, 19, GABRB3 {Epilepsy, childhood absence, susceptibility to, 5}, Epileptic encephalopathy, early infantile, 43, GABRG2 {Epilepsy, childhood absence, susceptibility to, 2}, Epilepsy, generalized, with febrile seizures plus, type 3, Febrile seizures, familial, 8, GAMT Cerebral creatine deficiency syndrome 2, GCK Diabetes mellitus, noninsulin dependent, late onset, Diabetes mellitus, permanent neonatal, Hyperinsulinemic hypoglycemia, familial, 3, MODY, type II, GCSH Glycine encephalopathy, GLDC Glycine encephalopathy, GLRA1 Hyperekplexia, hereditary 1 or recessive, GLRB Hyperekplexia 2, GLUD1 Hyperinsulinism hyperammonemia syndrome, GNAO1 Epileptic encephalopathy, early infantile, 17, GOSR2 Epilepsy, progressive myoclonic 6, GPC3 Simpson Golabi Behmel syndrome, type 1, Wilms tumor, somatic, GPHN Molybdenum cofactor deficiency C, GRIA3 Mental retardation 94,

6 GRIN1 Mental retardation 8, GRIN2A Epilepsy, focal, with speech disorder and with or without mental retardation, GRIN2B Epileptic encephalopathy, early infantile, 27, Mental retardation 6, GRN Aphasia, primary progressive, Ceroid lipofuscinosis, neuronal, 11, Frontotemporal lobar degeneration with ubiquitin positive inclusions, HADH 3 hydroxyacyl CoA dehydrogenase deficiency, Hyperinsulinemic hypoglycemia, familial, 4, HCN1 Epileptic encephalopathy, early infantile, 24, HDAC4 No phenotype HLCS Holocarboxylase synthetase deficiency, HNRNPU Epileptic encephalopathy, early infantile, 54, HSD17B10 HDS10 mitochondrial disease, HSD17B4 D bifunctional protein deficiency, Perrault syndrome 1, IDH2 D 2 hydroxyglutaric aciduria 2, IER3IP1 Microcephaly, epilepsy, and diabetes syndrome, IFIH1 Aicardi Goutieres syndrome 7, Singleton Merten syndrome 1, IQSEC2 Mental retardation 1/78, KANSL1 Koolen De Vries syndrome, KCNA1 Episodic ataxia/myokymia syndrome, KCNA2 Epileptic encephalopathy, early infantile, 32, KCNB1 Epileptic encephalopathy, early infantile, 26, KCNC1 Epilepsy, progressive myoclonic 7, KCNH1 Temple Baraitser syndrome, Zimmermann Laband syndrome 1, KCNJ10 Enlarged vestibular aqueduct, digenic, SESAME syndrome, KCNJ11 Diabetes mellitus, transient neonatal, 3, {Diabetes mellitus, type 2, susceptibility to}, Diabetes, permanent neonatal, with or without neurologic features, Hyperinsulinemic hypoglycemia, familial, 2, Maturity onset diabetes of the young, type 13, KCNMA1 Generalized epilepsy and paroxysmal dyskinesia, KCNQ2 Epileptic encephalopathy, early infantile, 7, Myokymia, Seizures, benign neonatal, 1,

7 KCNQ3 Seizures, benign neonatal, type 2, KCNT1 Epilepsy, nocturnal frontal lobe, 5, Epileptic encephalopathy, early infantile, 14, KCTD7 Epilepsy, progressive myoclonic 3, with or without intracellular inclusions, KDM5C Mental retardation, syndromic, Claes Jensen type, NEXMIF Mental retardation, X linked 98, KPTN Mental retardation 41, LGI1 Epilepsy, familial temporal lobe, 1, LIAS Hyperglycinemia, lactic acidosis, and seizures, MBD5 Mental retardation 1, MECP2 {Autism susceptibility 3}, Encephalopathy, neonatal severe, Mental retardation syndromic, Lubs type, Mental retardation, syndromic 13, Rett syndrome, Rett syndrome, atypical, Rett syndrome, preserved speech variant, MED12 Lujan Fryns syndrome, Ohdo syndrome, Opitz Kaveggia syndrome, MEF2C Chromosome 5q14.3 deletion syndrome, (4) Mental retardation, stereotypic movements, epilepsy, and/or cerebral malformations, MFSD8 Ceroid lipofuscinosis, neuronal, 7, Macular dystrophy with central cone involvement, MOCS1 Molybdenum cofactor deficiency A, MOCS2 Molybdenum cofactor deficiency B, MPDU1 Congenital disorder of glycosylation, type If, MTHFR Homocystinuria due to MTHFR deficiency, {Neural tube defects, susceptibility to}, {Schizophrenia, susceptibility to}, {Thromboembolism, susceptibility to}, {Vascular disease, susceptibility to} MTOR Focal cortical dysplasia, type II, somatic, Smith Kingsmore syndrome, NDUFA1 Mitochondrial complex I deficiency, NDUFA11 Mitochondrial complex I deficiency, NDUFAF1 Mitochondrial complex I deficiency, NDUFAF2 Leigh syndrome, , Mitochondrial Mitochondrial complex I deficiency,

8 NDUFAF3 Mitochondrial complex I deficiency, NDUFAF4 Mitochondrial complex I deficiency, NDUFAF5 Mitochondrial complex 1 deficiency, NDUFB3 Mitochondrial complex I deficiency, NDUFB9?Mitochondrial complex I deficiency, NDUFS1 Mitochondrial complex I deficiency, NDUFS2 Mitochondrial complex I deficiency, NDUFS3 Leigh syndrome due to mitochondrial complex I deficiency, Mitochondrial complex I deficiency, NDUFS4 Leigh syndrome, , Mitochondrial Mitochondrial complex I deficiency, NDUFS6 Mitochondrial complex I deficiency, NDUFV1 Mitochondrial complex I deficiency, NDUFV2 Mitochondrial complex I deficiency, NECAP1?Epileptic encephalopathy, early infantile, 21, NEDD4L Periventricular nodular heterotopia 7, NGLY1 Congenital disorder of deglycosylation, NHLRC1 Epilepsy, progressive myoclonic 2B (Lafora), NRXN1 Pitt Hopkins like syndrome 2, {Schizophrenia, susceptibility to, 17}, NUBPL Mitochondrial complex I deficiency, OFD1 Joubert syndrome 10, Orofaciodigital syndrome I, ?Retinitis pigmentosa 23, Simpson Golabi Behmel syndrome, type 2, OPHN1 Mental retardation, with cerebellar hypoplasia and distinctive facial appearance, PAK3 Mental retardation 30/47, PC Pyruvate carboxylase deficiency, PCDH19 Epileptic encephalopathy, early infantile, 9, PDHA1 Pyruvate dehydrogenase E1 alpha deficiency, PDHB Pyruvate dehydrogenase E1 beta deficiency, PDP1 Pyruvate dehydrogenase phosphatase deficiency, PDX1 {Diabetes mellitus, type II, susceptibility to}, MODY, type IV, Pancreatic agenesis 1, PET100 Mitochondrial complex IV deficiency, PEX1 Heimler syndrome 1, Peroxisome biogenesis disorder 1A (Zellweger), Peroxisome biogenesis disorder 1B (NALD/IRD),

9 PEX10 Peroxisome biogenesis disorder 6A (Zellweger), Peroxisome biogenesis disorder 6B, PEX12 Peroxisome biogenesis disorder 3A (Zellweger), Peroxisome biogenesis disorder 3B, PEX13 Peroxisome biogenesis disorder 11A (Zellweger), Peroxisome biogenesis disorder 11B, PEX14 Peroxisome biogenesis disorder 13A (Zellweger), PEX16 Peroxisome biogenesis disorder 8A (Zellweger), Peroxisome biogenesis disorder 8B, PEX19 Peroxisome biogenesis disorder 12A (Zellweger), PEX26 Peroxisome biogenesis disorder 7A (Zellweger), Peroxisome biogenesis disorder 7B, PEX3 Peroxisome biogenesis disorder 10A (Zellweger), ?Peroxisome biogenesis disorder 10B, PEX5 Peroxisome biogenesis disorder 2A (Zellweger), Peroxisome biogenesis disorder 2B, Rhizomelic chondrodysplasia punctata, type 5, PEX6 Heimler syndrome 2, Peroxisome biogenesis disorder 4A (Zellweger), Peroxisome biogenesis disorder 4B, PGAP3 Hyperphosphatasia with mental retardation syndrome 4, PHF6 Borjeson Forssman Lehmann syndrome, PHGDH Neu Laxova syndrome 1, Phosphoglycerate dehydrogenase deficiency, PIGA Multiple congenital anomalies hypotonia seizures syndrome 2, Paroxysmal nocturnal hemoglobinuria, somatic, PIGN Multiple congenital anomalies hypotonia seizures syndrome 1, PIGO Hyperphosphatasia with mental retardation syndrome 2, PIGT Multiple congenital anomalies hypotonia seizures syndrome 3, ?Paroxysmal nocturnal hemoglobinuria 2, PLA2G6 Infantile neuroaxonal dystrophy 1, Neurodegeneration with brain iron accumulation 2B, Parkinson disease 14, PLCB1 Epileptic encephalopathy, early infantile, 12, PLP1 Pelizaeus Merzbacher disease, Spastic paraplegia 2, PMM2 Congenital disorder of glycosylation, type Ia, PNKP Ataxia oculomotor apraxia 4, Microcephaly, seizures, and developmental delay,

10 PNPO Pyridoxamine 5' phosphate oxidase deficiency, POLG Mitochondrial DNA depletion syndrome 4A (Alpers type), Mitochondrial DNA depletion syndrome 4B (MNGIE type), Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), Progressive external ophthalmoplegia 1, Progressive external ophthalmoplegia 1, PPP2R1A Mental retardation 36, PPT1 Ceroid lipofuscinosis, neuronal, 1, PQBP1 Renpenning syndrome, PRICKLE1 Epilepsy, progressive myoclonic 1B, PRICKLE2 No phenotype PRRT2 Convulsions, familial infantile, with paroxysmal choreoathetosis, Episodic kinesigenic dyskinesia 1, Seizures, benign familial infantile, 2, PURA Mental retardation 31, PYCR2 Leukodystrophy, hypomyelinating, 10, QARS Microcephaly, progressive, seizures, and cerebral and cerebellar atrophy, RAB39B Mental retardation 72, ?Waisman syndrome, RARS2 Pontocerebellar hypoplasia, type 6, RNASEH2A Aicardi Goutieres syndrome 4, RNASEH2B Aicardi Goutieres syndrome 2, RNASEH2C Aicardi Goutieres syndrome 3, ROGDI Kohlschutter Tonz syndrome, RPS6KA3 Coffin Lowry syndrome, Mental retardation 19, RRM2B Mitochondrial DNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy), Mitochondrial DNA depletion syndrome 8B (MNGIE type), Progressive external ophthalmoplegia with mitochondrial DNA deletions 5, SAMHD1 Aicardi Goutieres syndrome 5, ?Chilblain lupus 2, SCARB2 Epilepsy, progressive myoclonic 4, with or without renal failure, SCN1A Epilepsy, generalized, with febrile seizures plus, type 2, Epileptic encephalopathy, early infantile, 6, Febrile seizures, familial, 3A, Migraine, familial hemiplegic, 3,

11 SCN1B Atrial fibrillation, familial, 13, Brugada syndrome 5, Cardiac conduction defect, nonspecific, Epilepsy, generalized, with febrile seizures plus, type 1, Epileptic encephalopathy, early infantile, 52, SCN2A Epileptic encephalopathy, early infantile, 11, Seizures, benign familial infantile, 3, SCN8A?Cognitive impairment with or without cerebellar ataxia, Epileptic encephalopathy, early infantile, 13, Seizures, benign familial infantile, 5, SIK1 Epileptic encephalopathy, early infantile, 30, SLC13A5 Epileptic encephalopathy, early infantile, 25, SLC16A1 Erythrocyte lactate transporter defect, Hyperinsulinemic hypoglycemia, familial, 7, Monocarboxylate transporter 1 deficiency, SLC19A3 Thiamine metabolism dysfunction syndrome 2 (biotin or thiamine responsive encephalopathy type 2), SLC25A1 Combined D 2 and L 2 hydroxyglutaric aciduria, SLC25A15 Hyperornithinemia hyperammonemia homocitrullinemia syndrome, SLC25A22 Epileptic encephalopathy, early infantile, 3, SLC2A1 Dystonia 9, {Epilepsy, idiopathic generalized, susceptibility to, 12}, GLUT1 deficiency syndrome 1, infantile onset, severe, GLUT1 deficiency syndrome 2, childhood onset, Stomatin deficient cryohydrocytosis with neurologic defects, SLC35A2 Congenital disorder of glycosylation, type IIm, SLC6A1 Myoclonic atonic epilepsy, SLC6A8 Cerebral creatine deficiency syndrome 1, SLC9A6 Mental retardation syndromic, Christianson type, SMARCA2 Nicolaides Baraitser syndrome, SMC1A Cornelia de Lange syndrome 2, SMS Mental retardation, Snyder Robinson type, SPTAN1 Epileptic encephalopathy, early infantile, 5, SRPX2?Rolandic epilepsy, mental retardation, and speech dyspraxia, ST3GAL3?Epileptic encephalopathy, early infantile, 15, Mental retardation 12, ST3GAL5 Salt and pepper developmental regression syndrome, STX1B Generalized epilepsy with febrile seizures plus, type 9, STXBP1 Epileptic encephalopathy, early infantile, 4,

12 SUOX Sulfite oxidase deficiency, SYN1 Epilepsy, with variable learning disabilities and behavior disorders, SYNGAP1 Mental retardation 5, SYP Mental retardation 96, SZT2 Epileptic encephalopathy, early infantile, 18, TANGO2 Metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration, TBC1D24 DOOR syndrome, Deafness 86, Deafness 65, Epileptic encephalopathy, early infantile, 16, Myoclonic epilepsy, infantile, familial, TBCE Encephalopathy, progressive, with amyotrophy and optic atrophy, Hypoparathyroidism retardation dysmorphism syndrome, Kenny Caffey syndrome, type 1, TCF4 Corneal dystrophy, Fuchs endothelial, 3, Pitt Hopkins syndrome, TDP2 Spinocerebellar ataxia 23, TPP1 Ceroid lipofuscinosis, neuronal, 2, Spinocerebellar ataxia 7, TREX1 Aicardi Goutieres syndrome 1, dominant and recessive, Chilblain lupus, {Systemic lupus erythematosus, susceptibility to}, Vasculopathy, retinal, with cerebral leukodystrophy, TRPM6 Hypomagnesemia 1, intestinal, TSC1 Focal cortical dysplasia, type II, somatic, Lymphangioleiomyomatosis, Tuberous sclerosis 1, TSC2?Focal cortical dysplasia, type II, somatic, Lymphangioleiomyomatosis, somatic, Tuberous sclerosis 2, TSEN54 Pontocerebellar hypoplasia type 2A, Pontocerebellar hypoplasia type 4, ?Pontocerebellar hypoplasia type 5, TUBA1A Lissencephaly 3, TUBB2A Cortical dysplasia, complex, with other brain malformations 5, TUBG1 Cortical dysplasia, complex, with other brain malformations 4, UBE3A Angelman syndrome,

13 WWOX Epileptic encephalopathy, early infantile, 28, Esophageal squamous cell carcinoma, somatic, Spinocrebellar ataxia 12, XK McLeod syndrome with or without chronic granulomatous disease, ZEB2 Mowat Wilson syndrome, Gene symbols according HGCN release used: "No phenotypes" indicates a gene without a current association phenotypes between "[ ]", indicate "nondiseases," mainly genetic variations that lead to apparently abnormal laboratory test values phenotypes between "{}", indicate risk factors phenotypes with a question mark, "?", before the disease name indicates an unconfirmed or possibly spurious mapping. The statistics above are based on a set of 50 samples Median depth is the median of the mean sequence depth over the protein coding exons of the transcript % Covered 10x describes the percentage of a gene s coding sequence that is covered at least 10x % Covered 20x describes the percentage of a gene s coding sequence that is covered at least 20x