Invitae Syndromic Neurodevelopmental Epilepsy Panel


Test description

The Invitae Syndromic Neurodevelopmental Epilepsy Panel analyzes 16 genes associated with early-onset developmental disorders in which epilepsy is a prominent finding. This panel provides comprehensive testing—particularly for the Rett/Angelman syndrome spectrum, which includes several disorders in the differential diagnosis. These syndromic disorders present with seizures, developmental delay, speech and language delays, intellectual disability, and variable congenital anomalies. These genes were curated based on the available evidence to date to provide comprehensive analysis for syndromic seizure disorders.

Given the clinical overlap between different syndromic epilepsy disorders, comprehensive panel testing allows for a more efficient evaluation of multiple conditions based on a single indication for testing. Individuals with clinical features suggestive of a syndromic neurodevelopmental epilepsy disorder may benefit from diagnostic genetic testing to establish or confirm a diagnosis, predict prognosis, inform medical management, and encourage testing of additional family members to inform reproductive risk.

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Primary panel (16 genes)


KANSL1: Deletion/duplication analysis is not offered for exons 2-3.
ROGDI: Deletion/duplication analysis is not offered for exons 1 or 2.
STXBP1: Deletion/duplication analysis is not offered for exons 1-3.

Alternative tests to consider

The Invitae Epilepsy Panel has been designed to provide a broad genetic analysis for 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.

  • Angelman syndrome
  • Angelman-like syndrome
  • Kohlschutter-Tonz syndrome
  • Koolen-DeVries syndrome
  • Mowat-Wilson syndrome
  • Ohtahara syndrome
  • Pitt-Hopkins syndrome
  • Rett syndrome
    • atypical Rett syndrome
    • congenital Rett syndrome
  • West syndrome

Epilepsy may occur as an isolated neurological finding, or it can be a prominent feature in syndromic neurodevelopmental disorders such as Rett, atypical Rett, congenital Rett, Angelman, Angelman-like, Pitt-Hopkins, Mowat-Wilson, West, Ohtahara, and Koolen-DeVries syndromes. These syndromic disorders typically present with seizures, developmental delay, speech and language delays, intellectual disability, and variable congenital anomalies. There can be significant overlap among some of these syndromes, particularly those in the Rett/Angelman syndrome phenotypic spectrum. A summary of the specific clinical features of some of these syndromes is provided in the table below as examples.

As defined by the International League Against Epilepsy, epilepsy is a common neurological disease that is characterized by two or more unprovoked seizures occurring 24 hours apart. Erratic electrical activity in the brain results in seizures, which may present as abnormal movements such as convulsions or jerks or as behaviors such as staring blankly. The location of the abnormal electrical activity in the brain is used to classify seizures into two categories: generalized and partial (also referred to as focal or local). Generalized seizures occur due to abnormal electrical activity originating from both hemispheres of the brain and include absence, myoclonic, clonic, tonic, and atonic seizures. The types of movements or behaviors that occur are used to further classify the type of generalized seizure. Partial (focal) seizures are caused by abnormal electrical activity restricted to a localized region of the brain and are further categorized as simple (conscious), complex (unconscious) and partial with secondary generalization (initially maintains consciousness but evolves into a loss of consciousness). In some cases, focal seizures eventually evolve into generalized seizures.

SyndromeClinical features
Rett/Atypical Rett syndromes regression in language and motor skills, stereotypic hand movements, ataxia, microcephaly, seizures
Angelman/Angelman-like syndromes severe developmental delay, absent or severely impaired speech, gait ataxia, microcephaly, characteristic EEG pattern, epilepsy, unique behavior (happy with outbursts of laughter; excitable), typical hand flapping movement, characteristic facial features including prominent chin, protruding tongue
Pitt-Hopkins syndrome severe intellectual disability, absent speech, breathing problems, seizures, microcephaly, characteristic features including coarse facial features, deep-set eyes, tented upper lip, widely spaced teeth, cup-shaped ears
Mowat-Wilson syndrome moderate to severe intellectual disability, expressive language delays, congenital heart defects, Hirschsprung disease, microcephaly, ataxia, short stature, eye abnormalities and agenesis of the corpus callosum, characteristic facial features including thick eyebrows, hypertelorism, downslanting palpebral fissures, elongated face
Koolen-DeVries syndrome (17q21.31 microdeletion syndrome) intellectual disability, hypotonia, characteristic dysmorphic features, epilepsy, congenital heart defects, urologic abnormalities, joint hypermobility,cryptorchidism, happy demeanor

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.

ConditionGene% attribution
Rett/atypical Rett syndromes MECP2 95% of females with Rett syndrome and 75% of females with atypical Rett syndrome
CDKL5 13% of atypical Rett syndrome cases
FOXG1 1% of Rett syndrome cases
MBD5 Rare cause of Rett-like syndrome
MEF2C Rare cause of Rett-like syndrome
Angelman/Angelman-like syndromes UBE3A 90% of Angelman syndrome cases*
SLC9A6 6% of Angelman syndrome cases
MBD5 Rare cause of Angelman-like syndrome (Christianson syndrome)
MECP2 Rare cause of Angelman-like syndrome
Mowat-Wilson ZEB2 98% of Mowat-Wilson syndrome cases**
Pitt-Hopkins TCF4 36% of Pitt-Hopkins syndrome cases
Other syndromic epilepsy conditions CNTNAP2 Unknown
DYNC1H1 Unknown
KANSL1 100% of Koolen-DeVries syndrome cases
NRXN1 Unknown
SCN8A Unknown
STXBP1 Unknown

*Approximately 80% are due to a maternal deletion of 15q11.2-15q13 or UPD; 11% is due to UBE3A mutations.

**The remaining 2% are large-scale rearrangements of the genomic region encompassing ZEB2.

Most syndromic neurodevelopmental epilepsy conditions are inherited in an autosomal dominant pattern. Some conditions, such as MECP2-related, CDKL5-related, and SLC9A6-related conditions, are X-linked. Others are inherited in an autosomal recessive or semidominant manner, such as NRXN1-related and CNTNAP2-related conditions.

The estimated prevalence for each syndrome is:

  • Rett/atypical Rett syndrome: 1 in 8500 by age 15 (among females)
  • Angelman/Angelman-like syndrome: 1 in 12,000 to 1 in 20,000
  • Mowat-Wilson syndrome: 1 in 50,000 to 1 in 70,000
  • Pitt-Hopkins syndrome: 1 in 11,000 to 1 in 300,000
  • Koolen-DeVries syndrome: 1 in 16,000
  • other syndromic epilepsy disorders: unknown

This test may be considered for individuals who have seizures, developmental delay, speech and language delays, intellectual disability, and congenital anomalies.

  1. Adam, MP, et al. Mowat-Wilson Syndrome. 2007 Mar 28. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301585
  2. Archer, HL, et al. CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients. J. Med. Genet. 2006; 43(9):729-34. PMID: 16611748
  3. Ardinger, HH, et al. Pitt-Hopkins Syndrome. 2012 Aug 30. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 22934316
  4. Ariani, F, et al. FOXG1 is responsible for the congenital variant of Rett syndrome. Am. J. Hum. Genet. 2008; 83(1):89-93. PMID: 18571142
  5. Bahi-Buisson, N, et al. Revisiting the phenotype associated with FOXG1 mutations: two novel cases of congenital Rett variant. Neurogenetics. 2010; 11(2):241-9. PMID: 19806373
  6. Brunetti-Pierri, N, et al. Duplications of FOXG1 in 14q12 are associated with developmental epilepsy, mental retardation, and severe speech impairment. Eur. J. Hum. Genet. 2011; 19(1):102-7. PMID: 20736978
  7. Cerruti, Mainardi, P, et al. Mowat-Wilson syndrome and mutation in the zinc finger homeo box 1B gene: a well defined clinical entity. J. Med. Genet. 2004; 41(2):e16. PMID: 14757866
  8. Christianson, AL, et al. X linked severe mental retardation, craniofacial dysmorphology, epilepsy, ophthalmoplegia, and cerebellar atrophy in a large South African kindred is localised to Xq24-q27. J. Med. Genet. 1999; 36(10):759-66. PMID: 10528855
  9. Christodoulou, J, Ho, G. MECP2-Related Disorders. 2001 Oct 03. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301670
  10. Cuddapah, VA, et al. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J. Med. Genet. 2014; 51(3):152-8. PMID: 24399845
  11. Dagli, AI, et al. Angelman Syndrome. 1998 Sep 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301323
  12. Fisher, RS, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014; 55(4):475-82. PMID: 24730690
  13. Garavelli, L, et al. Mowat-Wilson syndrome: facial phenotype changing with age: study of 19 Italian patients and review of the literature. Am. J. Med. Genet. A. 2009; 149A(3):417-26. PMID: 19215041
  14. Gilfillan, GD, et al. SLC9A6 mutations cause X-linked mental retardation, microcephaly, epilepsy, and ataxia, a phenotype mimicking Angelman syndrome. Am. J. Hum. Genet. 2008; 82(4):1003-10. PMID: 18342287
  15. Koolen, DA, de, Vries, BBA. KANSL1-Related Intellectual Disability Syndrome. 2010 Jan 26. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301783
  16. Le, Guen, T, et al. A FOXG1 mutation in a boy with congenital variant of Rett syndrome. Neurogenetics. 2011; 12(1):1-8. PMID: 20734096
  17. Li, MR, et al. MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome. J. Hum. Genet. 2007; 52(1):38-47. PMID: 17089071
  18. Lossie, AC, et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J. Med. Genet. 2001; 38(12):834-45. PMID: 11748306
  19. Marangi, G, et al. The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria. Am. J. Med. Genet. A. 2011; 155A(7):1536-45. PMID: 21671391
  20. Schroer, RJ, et al. Natural history of Christianson syndrome. Am. J. Med. Genet. A. 2010; 152A(11):2775-83. PMID: 20949524
  21. Takano, K, et al. Two percent of patients suspected of having Angelman syndrome have TCF4 mutations. Clin. Genet. 2010; 78(3):282-8. PMID: 20184619
  22. Zweier, M, et al. Mutations in MEF2C from the 5q14.3q15 microdeletion syndrome region are a frequent cause of severe mental retardation and diminish MECP2 and CDKL5 expression. Hum. Mutat. 2010; 31(6):722-33. PMID: 20513142
  23. de, Pontual, L, et al. Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. Hum. Mutat. 2009; 30(4):669-76. PMID: 19235238
  24. van, Bon, BW, et al. The 2q23.1 microdeletion syndrome: clinical and behavioural phenotype. Eur. J. Hum. Genet. 2010; 18(2):163-70. PMID: 19809484

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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Assay notes

UBE3A: Analysis includes sequencing and deletion analysis but does not detect uniparental disomy or imprinting center defects.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
CDKL5 NM_003159.2
CNTNAP2 NM_014141.5
DYNC1H1 NM_001376.4
FOXG1 NM_005249.4
KANSL1* NM_001193466.1
MBD5 NM_018328.4
MECP2 NM_004992.3, NM_001110792.1
MEF2C NM_002397.4
NRXN1 NM_001135659.1
ROGDI* NM_024589.2
SCN8A NM_014191.3
SLC9A6 NM_006359.2, NM_001042537.1
STXBP1* NM_003165.3
TCF4 NM_001083962.1
UBE3A NM_130838.1
ZEB2 NM_014795.3

KANSL1: Deletion/duplication analysis is not offered for exons 2-3.
ROGDI: Deletion/duplication analysis is not offered for exons 1 or 2.
STXBP1: Deletion/duplication analysis is not offered for exons 1-3.