PMC Epilepsy Panel

Associated Conditions
- Developmental and epileptic encephalopathy (DEE)
- Developmental disorders
- adenylosuccinate lyase (ADSL) deficiency
- Aicardi Goutieres syndrome
- ALG1-congenital disorder of glycosylation (CDG-Ik)
- ALG12-congenital disorder of glycosylation (CDG-Ig)
- ALG13-congenital disorder of glycosylation (CDG-Is)
- ALG6-congenital disorder of glycosylation (CDG-Ic)
- alpha-methylacyl-CoA racemase (AMACR) deficiency
- Angelman syndrome, Angelman-like syndrome, Christianson, syndrome
- arginase deficiency
- ARHEF9-related conditions (hereditary hyperekplexia, developmental and epileptic encephalopathy)
- aromatic L-amino acid decarboxylase (AADC) deficiency
- arthrogryposis, cleft palate, craniosynostosis, and intellectual disability
- ARX-related conditions (developmental and epileptic encephalopathy, West syndrome, lissencephaly with ambiguous genitalia)
- autosomal dominant lateral temporal epilepsy (ADLTE)
- CDKL5-related conditions (developmental and epileptic encephalopathy, West syndrome, atypical Rett syndrome, Angelman-like syndrome)
- cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss (CAPOS) syndrome, alternating hemiplegia of childhood type 2
- cerebellar atrophy with seizures and variable developmental delay
- cerebellar atrophy, visual impairment, and psychomotor retardation
- cerebral creatine deficiency syndrome due to arginine:glycine amidinotransferase (AGAT) deficiency
- cerebral folate deficiency
- cerebrotendinous xanthomatosis
- childhood onset epilepsy
- CLCN6-related neurodevelopmental syndrome
- CNTNAP2-related conditions (cortical dysplasia-focal epilepsy syndrome, Pitt-Hopkins-like syndrome)
- COG5-congenital disorder of glycosylation (CDG-IIi)
- combined oxidative phosphorylation deficiency
- combined saposin deficiency (PSAPD), metachromatic leukodystrophy due to saposin B deficiency, atypical Gaucher disease due to saposin C deficiency
- complex cortical dysplasia with other brain malformations
- congenital disorder of glycosylation (GPAA1-CDG)
- cortical malformation syndrome
- creatine transporter deficiency
- DEAF1-related neurodevelopmental disorders
- DEPDC5-related conditions (familial focal epilepsy with variable foci, nocturnal frontal lobe epilepsy)
- developmental and epileptic encephalopathy, early infantile epileptic encephalopathy
- dopa-responsive dystonia, GTP cyclohydrolase deficiency
- encephalopathy due to defective mitochondrial and peroxisomal fission
- epilepsy
- epilepsy and autism spectrum disorder
- epilepsy with variable learning disabilities and behavior disorders
- epilepsy, hearing loss, and intellectual disability syndrome
- facial dysmorphism, hypertrichosis, epilepsy, intellectual disability and gingival overgrowth syndrome
- familial encephalopathy with neuroserpin inclusion bodies
- familial focal epilepsy with variable foci
- familial paroxysmal nonkinesigenic dyskinesia
- FBXO11-related neurodevelopmental disorder
- GABA-transaminase (GABA-T) deficiency
- GABBR2-related conditions (developmental and epileptic encephalopathy, congenital Rett syndrome)
- GABRA1-related conditions (developmental and epileptic encephalopathy, childhood absence epilepsy, juvenile myoclonic epilepsy)
- GABRG2-related conditions (childhood absence epilepsy, generalized epilepsy with febrile seizures plus, familial febrile seizures, developmental and epileptic encephalopathy)
- generalized epilepsy and paroxysmal dyskinesia
- genetic epilepsy with febrile seizures plus
- Glass syndrome
- glucose transporter type 1 deficiency syndrome
- glycine encephalopathy
- glycosylphosphatidylinositol (GPI) biosynthesis defect 11
- GM3 synthase deficiency
- guanidinoacetate methyltransferase (GAMT) deficiency
- HCN1-related conditions (developmental and epileptic encephalopathy, genetic epilepsy with febrile seizures plus)
- HDAC8-related conditions (Cornelia de Lange syndrome, syndromic intellectual disability)
- hemophagocytic lymphohistiocytosis type 5
- hyperekplexia
- hyperglycinemia, lactic acidosis, and seizures, pyruvate dehydrogenase lipoic acid synthetase deficiency
- hyperphosphatasia with intellectual disability syndrome, Mabry syndrome
- hypomagnesemia, seizures and intellectual disability
- hypotonia with psychomotor retardation and characteristic facies
- infantile epilepsy, cataracts, and developmental delay
- infantile hypotonia with intellectual disability and characteristic facies
- infantile spasms, intractable epilepsy & cerebellar malformation
- infection-induced acute necrotizing encephalopathy
- inosine triphosphate pyrophosphohydrolase (ITPase) deficiency
- intellectual disability
- intractable neonatal myoclonus
- KCNQ2-related conditions (benign familial neonatal seizures, developmental and epileptic encephalopathy)
- KCNA1-related conditions (episodic ataxia type 1, epilepsy with or without ataxic episodes, paroxysmal kinesigenic dyskinesia)
- KCNH2-related conditions (long QT syndrome type 2, and short QT syndrome)
- KCNQ3-related conditions (benign familial neonatal seizures, developmental and epileptic encephalopathy)
- KIF1A associated neurological disorder
- Kleefstra syndrome
- Knobloch syndrome
- Kohlschutter syndrome
- Koolen-de Vries syndrome
- Leigh syndrome due to mitochondrial complex IV deficiency
- leukoencephalopathy with dystonia and motor neuropathy
- megaloblastic anemia due to dihydrofolate reductase deficiency
- Menkes disease
- metachromatic leukodystrophy
- microcephaly with seizures and cerebral and cerebellar atrophy
- microcephaly, epilepsy, and diabetes syndrome
- mitochondrial DNA depletion syndrome
- mitochondrial short-chain enoyl-CoA hydratase 1 deficiency
- molybdenum cofactor deficiency
- Mowat-Wilson syndrome
- mucopolysaccharidosis type IIIA , Sanfilippo syndrome A
- mucopolysaccharidosis type IIIB
- multiple sulfatase deficiency
- myoclonic epilepsy
- myoclonic epilepsy with ataxia
- myoclonic-atonic epilepsy (MAE), Doose syndrome
- neonatal-lethal rigidity and multifocal seizure syndrome
- neurodevelopmental delay and structural brain abnormalities
- neurodevelopmental disorder
- neurodevelopmental disorder with ataxic gait, absent speech, and decreased cortical white matter
- neurodevelopmental disorder with craniofacial abnormalities
- neurodevelopmental disorder with movement abnormalities, abnormal gait, and autistic features
- neurodevelopmental disorder with seizures and nonepileptic hyperkinetic movements
- neuronal ceroid lipofuscinosis
- NGLY1-congenital disorder of glycosylation (CDG-Iv)
- Niemann-Pick disease type C
- nocturnal frontal lobe epilepsy
- occipital cortical malformations
- PAFAH1B1-related conditions (lissencephaly including Miller-Dieker syndrome, isolated lissencephaly sequence, and subcortical band heterotopia)
- periventricular heterotopia
- periventricular nodular heterotopia
- peroxisomal fatty acyl-CoA reductase 1 disorder
- phosphoglycerate dehydrogenase deficiency, Neu-Laxova syndrome
- phosphoserine aminotransferase (PSAT) deficiency, Neu-Laxova syndrome type 2
- phosphoserine phosphatase deficiency
- Pierpont syndrome
- PIGA-congenital disorder of glycosylation
- PIGB-congenital disorder of glycosylation
- PIGG-congenital disorder of glycosylation
- PIGN-congenital disorder of glycosylation
- PIGO-congenital disorder of glycosylation
- PIGQ-congenital disorder of glycosylation
- Pitt-Hopkins syndrome, Pitt-Hopkins-like syndrome
- POLG-related conditions
- polyhydramnios, megalencephaly, and symptomatic epilepsy (PMSE) syndrome
- pontocerebellar hypoplasia
- progressive encephalopathy with edema, hypsarrhythmia, and optic atrophy-like syndrome (PEHO-like syndrome)
- progressive myoclonic epilepsy
- PRRT2-related conditions (episodic kinesigenic dyskinesia, benign familial infantile seizures, familial infantile convulsions with paroxysmal choreoathetosis)
- PTEN hamartoma tumor syndrome (PHTS), Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, PTEN-related autism spectrum disorder
- PURA syndrome
- pyridoxal 5′-phosphate-dependent epilepsy
- pyridoxine-dependent epilepsy
- recurrent metabolic crises with rhabdomyolysis, cardiac arrhythmias and neurodegeneration
- RELN-related conditions (lissencephaly, autosomal dominant lateral temporal lobe epilepsy)
- Rett syndrome, atypical Rett syndrome, congenital Rett syndrome
- RFT1-congenital disorder of glycosylation (CDG-In)
- Schinzel-Giedion syndrome
- SCN1A-related conditions (febrile seizures, genetic epilepsy with febrile seizures plus, Dravet syndrome, intractable childhood epilepsy with generalized tonic-clonic seizures)
- SCN1B-related conditions (generalized epilepsy with febrile seizures, developmental and epileptic encephalopathy)
- SCN2A-related conditions (benign familial neonatal-infantile seizures, developmental and epileptic encephalopathy, episodic ataxia, intellectual disability)
- seizures, cortical blindness, and microcephaly syndrome
- SeSAME syndrome
- SGCE-related conditions (myoclonic dystonia, generalized epilepsy)
- SLC25A2 -congenital disorder of glycosylation (CDG-IIm)
- SMC1A-related conditions (Cornelia de Lange syndrome, developmental and epileptic encephalopathy, holoprosencephaly)
- Smith-Kingsmore syndrome
- Smith-Magenis syndrome
- spinal muscular atrophy with progressive myoclonic epilepsy
- succinic semialdehyde dehydrogenase (SSADH) deficiency
- sulfite oxidase deficiency
- syndromic epilepsy
- Tay-Sachs disease, beta-hexosaminidase A (HEXA) deficiency
- TBC1D24-related conditions (developmental and epileptic encephalopathy, familial infantile myoclonic epilepsy, progressive myoclonic epilepsy)
- Temtamy syndrome
- tetrahydrobiopterin-deficient hyperphenylalaninemia due to quinoid dihydropteridine reductase (DHPR) deficiency
- thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type
- thiamine metabolism dysfunction syndrome, biotin-responsive basal ganglia disease
- tuberous sclerosis complex
- tyrosine hydroxylase (TH) deficiency
- Unverricht-Lundborg syndrome
- WDR45-related conditions (beta-propeller protein-associated neurodegeneration, developmental and epileptic encephalopathy, Rett syndrome)
- Zellweger spectrum disorder
- Zimmermann-Laband syndrome, Temple-Baraitser syndrome
- Biotinidase Deficiency
- Biotin Deficiency

Methodology

Targeted Exome/ Slice Exome (Next Generation Sequencing including Copy Number Variation)

Coverage

120x

Assay Information
- ARX: Analysis is validated to detect polyalanine expansions but sensitivity may be reduced.
- ATP1A1: Deletion/duplication analysis is not offered for exon 1.
- CACNA1A: Trinucleotide repeat expansions are not determined on this assay.
- CACNA1B: Deletion/duplication and sequencing analysis is not offered for exons 1-3.
- CSTB: Dodecamer repeat numbers in the 5' UTR are not determined.
- DDC: Deletion/duplication analysis is not offered for exons 10-11.
- DDX3X: Sequencing analysis is not offered for exon 3.
- DENND5A: Sequencing analysis for exons 9 includes only cds +/- 10 bp.
- DMXL2: Deletion/duplication analysis is not offered for exon 2.
- FASN: Sequencing analysis for exons 7 includes only cds +/- 10 bp.
- FGF12: Sequencing analysis for exons 4 includes only cds +/- 0 bp.
- KANSL1: Deletion/duplication and sequencing analysis is not offered for exons 2-3.
- PACS1: Sequencing analysis is not offered for exon 1.
- PCLO: Sequencing analysis for exons 2 includes only cds +/- 0 bp.
- PIGB: Deletion/duplication analysis is not offered for exon 9.
- PPT1: Analysis includes the large| mostly intronic deletion NM_000310.3:c.124+1215_235-102del3627 as well as the intronic variant NM_000310.3:c.125-15T>G.
- PSPH: Deletion/duplication and sequencing analysis is not offered for exons 4-5.
- PTEN: Sequencing analysis for exons 8 includes only cds +/- 10 bp.
- RANBP2: Deletion/duplication and sequencing analysis is not offered for exons 1-11| 15-29.
- RNF13: Sequencing analysis is not offered for exon 4.
- SCN8A: Analysis includes exon 6 of NM_001330260.1.
- SIK1: Deletion/duplication analysis is not offered for exons 13-14.
- SLC9A6: Sequencing analysis for exons 14 includes only cds +/- 10 bp.
- TSC1: Sequencing analysis for exons 21 includes only cds +/- 10 bp.
- TSFM: Sequencing analysis is not offered for exon 5.
- TUBB2A: Deletion/duplication and sequencing analysis is not offered for exon 2.
- UBE3A: Analysis includes sequencing and deletion/duplication analysis but does not detect uniparental disomy or imprinting center defects.
- ZSWIM6: Sequencing analysis is not offered for exon 1.

Ordering information

Turnaround Time: 10 business days

Preferred Speciment: Saliva Kits (available upon request)

Alternate Specimens: Nail clippings or 3-mL whole blood in purple top EDTA tube

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Limitations

All sequencing technologies have limitations. A negative result from this analysis does not rule out a possible genetic diagnosis as some variants may not be detected by this test. This test is not designed to detect low level mosaicism, structural rearrangements, indels >40bp, deep intronic variants of unknown clinical significance, or large cytogenetic CNVs. Certain inherent qualities of the human genome, for example repetitive regions/homopolymers, GC rich, pseudogenes, and rare polymorphisms, pose significant technical challenges such as sequence misalignment that may potentially impact the accuracy of the results. False negative results may also occur in the setting of allogeneic bone marrow, stem cell transplantation, active or chronic hematologic conditions, recent blood transfusions, suboptimal DNA quality or PCR trace contamination. Other potential sources of error include sample mix-ups and clerical issues.

References
- 1. Richards S et al. Genetics in medicine. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. 2015 May;17(5):405-24 (PMID: 25741868)
- 2. GnomAD (gnomAD)
- 3. CSPEC (ClinGen variant classification rules registry) Criteria Specification Registry
- 4. Normal copy number variation in healthy individuals database of genomic variants: http://dgv.tcag.ca/dgv/app/home
- 5. Riggs, E.R., Andersen, E.F., Cherry, A.M. et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med 22, 245–257 (2020). https://doi.org/10.1038/s41436-019-0686-8
- 6. Landrum MJ, Lee JM, Riley GR, Jang W, Rubinstein WS, Church DM, Maglott DR. ClinVar: public archive of relationships among sequence variation and human phenotype. Nucleic Acids Res. 2014 Jan 1;42(1):D980-5. doi: 10.1093/nar/gkt1113. PubMed PMID: 24234437.
- 7. Online Mendelian Inheritance in Man, OMIM®. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University (Baltimore, MD), Copyright® 1966-2012. World Wide Web URL: http://omim.org.
- 8. http://tinyurl.com/ACMGv4 (ACMG/ Clingen draft Interpretation SOP); clingen_variant-curation_sopv1.pdf

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Test Description

Associated Conditions

Methodology

Coverage

Assay Information

Ordering information

Limitations

References

Tagged Genes