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  • Test code: 03402
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    10–21 calendar days (14 days on average)
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    3mL whole blood in a purple-top tube
  • Alternate specimens:
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  1. Test Catalog
  2. Invitae Early Infantile Epileptic Encephalopathy Panel

Invitae Early Infantile Epileptic Encephalopathy Panel

Test description

The Invitae Early Infantile Epileptic Encephalopathy Panel analyzes up to 69 genes that are associated with an onset of seizures within the first 3 months of life. Significant clinical and genetic heterogeneity exists in early infantile epileptic encephalopathy (EIEE, also known as Ohtahara syndrome), making it difficult to use phenotype as the sole criterion to point to a definitive cause. Comprehensive panel testing allows for an efficient evaluation of multiple genes based on a single clinical indication for testing. Identification of the molecular basis of EIEE in an affected individual may confirm diagnosis, determine prognosis, inform treatment options, and encourage testing of additional family members to inform reproductive risk.

Genes tested

Primary panel

ALDH7A1 ARHGEF9 ARX BRAT1 CACNA2D2 CASK CDKL5 CHD2 CLCN4 DNM1 DOCK7 EEF1A2 FARS2 FOLR1 FRRS1L GABBR2 GABRA1 GABRB3 GNAO1 GRIN1 GRIN2A GRIN2B HCN1 HNRNPU IER3IP1 KCNA2 KCNB1 KCNMA1 KCNQ2 KCNQ3 KCNT1 PCDH19 PIGA PIGN PIGO PLCB1 PNKP PNPO PURA SCN1A SCN2A SCN8A SCN9A SIK1 SLC12A5 SLC13A5 SLC25A12 SLC25A22 SLC2A1 SLC35A2 SLC6A1 SMC1A SPTAN1 STXBP1 SYNGAP1 SZT2 TBC1D24 WDR45 WWOX

Add-on Preliminary-evidence Genes for Early Infantile Epileptic Encephalopathy

ARHGEF15 ATP1A2 COQ4 GPHN KCNH5 MTOR NECAP1 NEDD4L SCN1B ST3GAL3

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

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Primary panel (59 genes)

ALDH7A1 ARHGEF9 ARX BRAT1 CACNA2D2 CASK CDKL5 CHD2 CLCN4 DNM1 DOCK7 EEF1A2 FARS2 FOLR1 FRRS1L GABBR2 GABRA1 GABRB3 GNAO1 GRIN1 GRIN2A GRIN2B HCN1 HNRNPU IER3IP1 KCNA2 KCNB1 KCNMA1 KCNQ2 KCNQ3 KCNT1 PCDH19 PIGA PIGN PIGO PLCB1 PNKP PNPO PURA SCN1A SCN2A SCN8A SCN9A SIK1 SLC12A5 SLC13A5 SLC25A12 SLC25A22 SLC2A1 SLC35A2 SLC6A1 SMC1A SPTAN1 STXBP1 SYNGAP1 SZT2 TBC1D24 WDR45 WWOX

Panel details and technical assay limitations
Add-on Preliminary-evidence Genes for Early Infantile Epileptic Encephalopathy (10 genes)

Preliminary-evidence genes currently have early evidence of a clinical association with the specific disease covered by this test. Some clinicians may wish to include genes which do not currently have a definitive clinical association, but which may prove to be clinically significant in the future. These genes can be added at no additional charge. Visit our Preliminary-evidence genes page to learn more.

ARHGEF15 ATP1A2 COQ4 GPHN KCNH5 MTOR NECAP1 NEDD4L SCN1B ST3GAL3

Panel details and technical assay limitations

Alternative tests to consider

The Invitae Epilepsy Panel has been designed to provide a broad genetic analysis of epilepsy disorders. Depending on the individual’s clinical and family history, this broader panel may be appropriate and can be ordered at no additional cost.

Clinical information

  • benign familial neonatal-infantile seizures
  • benign familial neonatal seizures
  • childhood absence epilepsy
  • cerebral folate deficiency
  • Dravet syndrome
  • early infantile epileptic encephalopathy (EIEE)
  • generalized epilepsy with febrile seizures plus (GEFS+)
  • generalized epilepsy and paroxysmal dyskinesia
  • GLUT1 deficiency syndrome
  • hyperphosphatasia with intellectual disability syndrome
  • juvenile myoclonic epilepsy
  • microcephaly, epilepsy, and diabetes syndrome (MEDS)
  • multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1)
  • multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2)
  • neonatal-lethal rigidity and multifocal seizure syndrome (RFMSL)
  • pyridoxine-dependent epilepsy

Early infantile epileptic encephalopathies are severe early-onset forms of epilepsy. Affected children suffer from intractable tonic seizures, characteristic suppression-burst patterns on electroencephalogram (EEG), and severe motor and intellectual impairment. The majority of children with EIEE experience seizures within the first three months of life. They can present with a variety of seizure types that may occur up to hundreds of times a day and independent of the sleep cycle. Some may also exhibit tremor, ataxia, or dystonia. The clinical presentation often evolves into West syndrome and Lennox-Gastaut syndrome. While brain malformations and metabolic disease can also cause EIEE, idiopathic cases are thought to be of genetic origin.

The most common types of seizures observed in individuals with EIEE are isolated or clustered tonic spasms. Additional seizure types observed include asymmetric tonic and focal seizures. The classic EEG presentation observed in affected individuals is a suppression-burst pattern consisting of alternating medium-high voltage bursts followed by flat suppression interburst intervals. The majority of EIEE cases evolve into West syndrome between 4–6 months of age, with continuing infantile spasms and the observation of developmental delays and a characteristic EEG pattern of hypsarrhythmia. Later in childhood, between 1–3 years of age, EIEE can develop into Lennox-Gastaut syndrome (PMID: 19153375, 23027099, 22830456). Along with severe motor and intellectual impairment, children with EIEE can sometimes also exhibit tremor, ataxia, or dystonia.

The clinical sensitivity of this test is dependent on the patient’s underlying genetic condition. For each condition, the table below shows the percentage of clinical cases in which a pathogenic variant is expected to be identified through sequence and deletion/duplication analysis of the genes on this panel.

Sensitivity by clinical conditionGene
71% of epileptic encephalopathy (PMID: 23708187) CDKL5, CHD2, KCNQ2, PCDH19, SCN1A, SCN2A, SYNGAP1
90% of benign familial epilepsy (PMID: 23360469) KCNQ2, KCNQ3, SCN2A
75% of Dravet syndrome (PMID: 19214208, 20713952) PCDH19, SCN1A
35% of EIEE (Ohtahara syndrome) (PMID: 20100225) STXBP1
10% of early onset absence epilepsy and 90% of GLUT1 deficiency encephalopathy (PMID: 20100225) SLC2A1
Unknown percentage of rare subtypes of EIEE ALDH7A1, ARHGEF9, ARX, BRAT1, CACNA1A, CACNA2D2, CASK, CLCN4, DNM1, DOCK7, EEF1A2, FARS2, FOLR1, FRRS1L, GABBR2, GABRA1, GABRB3, GNAO1, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1,KCNMA1, KCNT1, PIGA, PIGN, PIGO, PLCB1, PNKP, PNPO, PURO, SCN8A, SCN9A, SIK1, SLC12A5, SLC13A5, SLC25A12, SLC25A22, SPTAN1, SZT2, TBC1D24, WDR45, WWOX

EIEE can occur in several inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked dominant.

The estimated prevalence for each condition is:

  • EIEE: 1 in 100,000 births to 1 in 50,000 births
  • pyridoxine-dependent epilepsy: 1 in 700,000 births
  • West syndrome: 1–9 in 100,000 births
  • Lennox-Gastaut syndrome: 1–5 in 100,000
  • ISSX: 2–3 in 100,000
  • Dravet syndrome: <1 in 40,000 worldwide

This test may be considered for individuals who have recurrent infantile seizures or spasms.

  1. Carvill, GL, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 2013; 45(7):825-30. PMID: 23708187
  2. Depienne, C, et al. Genes in infantile epileptic encephalopathies. In: Noebels, JL, et al, editors. Jasper's Basic Mechanisms of the Epilepsies (Internet). National Center for Biotechnology Information (US). PMID: 22787626
  3. Gospe, SM. Pyridoxine-Dependent Epilepsy. 2001 Dec 07. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1486/ PMID: 20301659
  4. Bellini, G, et al. KCNQ2-Related Disorders. 2010 Apr 27. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK32534/ PMID: 20437616
  5. Bellini, G, et al. KCNQ3-Related Disorders. 2014 May 22. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK201978/ PMID: 24851285
  6. Mercimek-Mahmutoglu, S, et al. Creatine Deficiency Syndromes. 2009 Jan 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301745
  7. Saitsu, H, et al. Haploinsufficiency of STXBP1 and Ohtahara syndrome. In: Noebels, JL, et al, editors. Jasper's Basic Mechanisms of the Epilepsies (Internet). National Center for Biotechnology Information (US). PMID: 22787616
  8. Baxter, P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch. Dis. Child. 1999; 81(5):431-3. PMID: 10519720
  9. Trevathan, E, et al. The descriptive epidemiology of infantile spasms among Atlanta children. Epilepsia. 1999; 40(6):748-51. PMID: 10368073
  10. Ottman, R, et al. Genetic testing in the epilepsies--report of the ILAE Genetics Commission. Epilepsia. 2010; 51(4):655-70. doi: 10.1111/j.1528-1167.2009.02429.x. PMID: 20100225
  11. Zara, F, et al. Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia. 2013; 54(3):425-36. PMID: 23360469
  12. Depienne, C, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 2009; 5(2):e1000381. PMID: 19214208
  13. Marini, C, et al. Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology. 2010; 75(7):646-53. PMID: 20713952
  14. Deprez, L, et al. Genetics of epilepsy syndromes starting in the first year of life. Neurology. 2009; 72(3):273-81. PMID: 19153375
  15. Nordli, DR. Epileptic encephalopathies in infants and children. J Clin Neurophysiol. 2012; 29(5):420-4. PMID: 23027099
  16. Tavyev, Asher, YJ, Scaglia, F. Molecular bases and clinical spectrum of early infantile epileptic encephalopathies. Eur J Med Genet. 2012; 55(5):299-306. PMID: 22548976
  17. Wheless, JW, et al. Infantile spasms (West syndrome): update and resources for pediatricians and providers to share with parents. BMC Pediatr. 2012; 12:108. PMID: 22830456

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Assay notes

ARX: Analysis is validated to detect polyalanine expansions but sensitivity may be reduced in heterozygous females. Family variant testing in female individuals is available when there is a confirmed expansion in a male relative.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
ALDH7A1 NM_001182.4
ARHGEF15 NM_173728.3
ARHGEF9 NM_015185.2; NM_001173479.1
ARX* NM_139058.2
ATP1A2 NM_000702.3
BRAT1 NM_152743.3
CACNA2D2 NM_006030.3
CASK NM_003688.3
CDKL5 NM_003159.2
CHD2 NM_001271.3
CLCN4 NM_001830.3
COQ4 NM_016035.4
DNM1 NM_004408.3
DOCK7 NM_001271999.1
EEF1A2 NM_001958.3
FARS2 NM_006567.3
FOLR1 NM_016725.2
FRRS1L NM_014334.2
GABBR2 NM_005458.7
GABRA1 NM_000806.5
GABRB3 NM_000814.5
GNAO1 NM_020988.2
GPHN NM_020806.4
GRIN1 NM_007327.3
GRIN2A NM_000833.4
GRIN2B NM_000834.3
HCN1 NM_021072.3
HNRNPU NM_031844.2
IER3IP1 NM_016097.4
KCNA2 NM_004974.3
KCNB1 NM_004975.2
KCNH5 NM_139318.4
KCNMA1 NM_002247.3
KCNQ2 NM_172107.2
KCNQ3 NM_004519.3
KCNT1 NM_020822.2
MTOR NM_004958.3
NECAP1 NM_015509.3
NEDD4L NM_015277.5
PCDH19 NM_001184880.1
PIGA NM_002641.3
PIGN NM_176787.4
PIGO NM_032634.3
PLCB1 NM_015192.3
PNKP NM_007254.3
PNPO NM_018129.3
PURA NM_005859.4
SCN1A NM_001165963.1
SCN1B NM_199037.3
SCN2A NM_021007.2
SCN8A* NM_014191.3
SCN9A NM_002977.3
SIK1 NM_173354.3
SLC12A5 NM_020708.4
SLC13A5 NM_177550.4
SLC25A12 NM_003705.4
SLC25A22 NM_024698.5
SLC2A1 NM_006516.2
SLC35A2 NM_001042498.2
SLC6A1 NM_003042.3
SMC1A NM_006306.3
SPTAN1 NM_001130438.2
ST3GAL3 NM_006279.3
STXBP1 NM_003165.3
SYNGAP1 NM_006772.2
SZT2 NM_015284.3
TBC1D24 NM_001199107.1
WDR45 NM_007075.3
WWOX NM_016373.3

ARX: Analysis is validated to detect polyalanine expansions but sensitivity may be reduced.
SCN8A: Analysis includes exon 6 of NM_001330260.1.

References

  1. Baxter, P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch. Dis. Child. 1999; 81(5):431-3. PMID: 10519720
  2. Bellini, G, et al. KCNQ2-Related Disorders. 2010 Apr 27. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK32534/ PMID: 20437616
  3. Bellini, G, et al. KCNQ3-Related Disorders. 2014 May 22. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK201978/ PMID: 24851285
  4. Carvill, GL, et al. Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1. Nat. Genet. 2013; 45(7):825-30. PMID: 23708187
  5. Depienne, C, et al. Genes in infantile epileptic encephalopathies. In: Noebels, JL, et al, editors. Jasper's Basic Mechanisms of the Epilepsies (Internet). National Center for Biotechnology Information (US). PMID: 22787626
  6. Depienne, C, et al. Sporadic infantile epileptic encephalopathy caused by mutations in PCDH19 resembles Dravet syndrome but mainly affects females. PLoS Genet. 2009; 5(2):e1000381. PMID: 19214208
  7. Deprez, L, et al. Genetics of epilepsy syndromes starting in the first year of life. Neurology. 2009; 72(3):273-81. PMID: 19153375
  8. Gospe, SM. Pyridoxine-Dependent Epilepsy. 2001 Dec 07. In: Pagon, RA, et al, editors. GeneReviews (Internet). University of Washington, Seattle; Available from: http://www.ncbi.nlm.nih.gov/books/NBK1486/ PMID: 20301659
  9. Marini, C, et al. Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology. 2010; 75(7):646-53. PMID: 20713952
  10. Mercimek-Mahmutoglu, S, et al. Creatine Deficiency Syndromes. 2009 Jan 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301745
  11. Nordli, DR. Epileptic encephalopathies in infants and children. J Clin Neurophysiol. 2012; 29(5):420-4. PMID: 23027099
  12. Ottman, R, et al. Genetic testing in the epilepsies--report of the ILAE Genetics Commission. Epilepsia. 2010; 51(4):655-70. doi: 10.1111/j.1528-1167.2009.02429.x. PMID: 20100225
  13. Saitsu, H, et al. Haploinsufficiency of STXBP1 and Ohtahara syndrome. In: Noebels, JL, et al, editors. Jasper's Basic Mechanisms of the Epilepsies (Internet). National Center for Biotechnology Information (US). PMID: 22787616
  14. Tavyev, Asher, YJ, Scaglia, F. Molecular bases and clinical spectrum of early infantile epileptic encephalopathies. Eur J Med Genet. 2012; 55(5):299-306. PMID: 22548976
  15. Trevathan, E, et al. The descriptive epidemiology of infantile spasms among Atlanta children. Epilepsia. 1999; 40(6):748-51. PMID: 10368073
  16. Wheless, JW, et al. Infantile spasms (West syndrome): update and resources for pediatricians and providers to share with parents. BMC Pediatr. 2012; 12:108. PMID: 22830456
  17. Zara, F, et al. Genetic testing in benign familial epilepsies of the first year of life: clinical and diagnostic significance. Epilepsia. 2013; 54(3):425-36. PMID: 23360469

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