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.
Note: Analysis of ARX is validated to detect polyalanine expansions but sensitivity may be reduced.
SCN8A: Analysis includes exon 6 of NM_001330260.1.
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.
Order test
Primary panel (59 genes)
Customized gene selection (0 included, 0 excluded)
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 (10 genes)
Customized gene selection (0 included, 0 excluded)
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
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. Re-requisition from this test to the Invitae Epilepsy Panel is available.
Clinical information
Disorders tested
- 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
Clinical description
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.
Clinical sensitivity
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 condition | Gene |
|---|---|
| 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 |
Inheritance
EIEE can occur in several inheritance patterns, including autosomal dominant, autosomal recessive, and X-linked dominant.
Prevalence/Incidence
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
Considerations for testing
This test may be considered for individuals who have recurrent infantile seizures or spasms.
References
- 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
- 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
- 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
- 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
- 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
- Deprez, L, et al. Genetics of epilepsy syndromes starting in the first year of life. Neurology. 2009; 72(3):273-81. PMID: 19153375
- 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
- Nordli, DR. Epileptic encephalopathies in infants and children. J Clin Neurophysiol. 2012; 29(5):420-4. PMID: 23027099
- 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
- 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
- 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
- Marini, C, et al. Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology. 2010; 75(7):646-53. PMID: 20713952
- 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
- 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
- Baxter, P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch. Dis. Child. 1999; 81(5):431-3. PMID: 10519720
- Trevathan, E, et al. The descriptive epidemiology of infantile spasms among Atlanta children. Epilepsia. 1999; 40(6):748-51. PMID: 10368073
- 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
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 and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
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.
| 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; NM_001037.4 | ||
| SCN2A | NM_021007.2 | ||
| SCN8A | NM_014191.3; NM_001330260.1 | ||
| 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.
SIK1: Deletion/duplication analysis is not offered for exons 13-14.
References
- Baxter, P. Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK. Arch. Dis. Child. 1999; 81(5):431-3. PMID: 10519720
- 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
- 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
- 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
- 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
- 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
- Deprez, L, et al. Genetics of epilepsy syndromes starting in the first year of life. Neurology. 2009; 72(3):273-81. PMID: 19153375
- 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
- Marini, C, et al. Protocadherin 19 mutations in girls with infantile-onset epilepsy. Neurology. 2010; 75(7):646-53. PMID: 20713952
- 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
- Nordli, DR. Epileptic encephalopathies in infants and children. J Clin Neurophysiol. 2012; 29(5):420-4. PMID: 23027099
- 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
- 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
- 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
- Trevathan, E, et al. The descriptive epidemiology of infantile spasms among Atlanta children. Epilepsia. 1999; 40(6):748-51. PMID: 10368073
- 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
- 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
