Invitae Rett and Angelman Syndromes and Related Disorders Panel

Ordering
  • Test code: 03404
  • Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit
Billing

Test description

The Invitae Rett and Angelman Syndromes and Related Disorders Panel analyzes up to 25 genes associated with early-onset developmental disorders related to the Rett/Angelman spectrum. These syndromic disorders present with seizures, developmental delay, speech and language delays, intellectual disability, and variable congenital anomalies. Some include characteristic dysmorphic features. These genes were curated based on the available evidence to date to provide comprehensive analysis for syndromic seizure disorders.

Given the clinical overlap between disorders in the Rett/Angelman spectrum, 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 disorder in the Rett/Angelman spectrum may benefit from genetic testing to establish or confirm a diagnosis, determine prognosis, inform medical management, and encourage testing of additional family members to inform reproductive risk.

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Primary panel (22 genes)

ADSL ALDH5A1 ATRX CDKL5 CNTNAP2 DYRK1A EHMT1 FOXG1 IQSEC2 KANSL1 MBD5 MECP2 MEF2C NGLY1 NRXN1 SATB2 SCN8A SLC9A6 STXBP1 TCF4 UBE3A ZEB2

KANSL1: Deletion/duplication analysis is not offered for exons 2-3.
SCN8A: Analysis includes exon 6 of NM_001330260.1.

Add-on Preliminary-evidence Genes for Rett and Angelman Syndromes and Related Disorders (3 genes)

In addition to the primary panel, clinicians can also choose to include three genes that have preliminary evidence of association with early-onset developmental disorders that overlap with Rett and Angelman syndromes. However, some clinicians may wish to include genes that may prove to be clinically significant in the future. Visit our Preliminary-evidence genes page to learn more.

GABRD TBL1XR1 WDR45

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.

  • adenylosuccinate lyase deficiency
  • alpha-thalassemia X-linked intellectual disability (ATRX) syndrome
  • Angelman syndrome
    • Angelman-like syndrome
  • cortical dysplasia-focal epilepsy syndrome (CDFES)
  • idiopathic generalized epilepsy
  • intellectual disability
  • Kleefstra syndrome
  • Koolen-de Vries syndrome
  • Mowat-Wilson syndrome
  • NGLY1-congenital disorder of glycosylation
  • Glass syndrome
  • Pitt-Hopkins syndrome
    • Pitt-Hopkins-like syndrome
  • SCN8A-related early infantile epileptic encephalopathy
  • succinic semialdehyde dehydrogenase (SSADH) deficiency
  • Rett syndrome
    • atypical Rett syndrome
    • congenital Rett syndrome

Rett and Angelman syndromes are classic early-onset neurodevelopmental disorders. Rett syndrome primarily affects girls and is characterized by rapid regression of motor and speech skills between 6-18 months of age following a period of normal development. Stereotypic hand movements and seizures are common in Rett syndrome, along with variably present findings including autism, episodic apnea, gait ataxia and apraxia, and microcephaly. In some rare cases, favorable X-inactivation may result only in mild intellectual impairment in girls with Rett syndrome. There are variant forms of Rett syndrome as well. A congenital form manifests with classic Rett signs at birth or soon after but overt regression is not a hallmark. Another form manifests around 6 months of age but is mostly characterized by seizures. The main X-linked form of Rett syndrome due to MECP2 mutations is seen almost exclusively in girls and is prenatally lethal in males. However, in rare surviving males, the clinical presentation is extremely severe with overt encephalopathy, hypoventilation, and microcephaly, and failure to survive beyond 2-3 years of age.

Pathogenic changes in a Rett syndrome-related gene have been identified in some children suspected to have Angelman syndrome, pointing to an important clinical overlap. The Angelman syndrome phenotype may often be diagnosed after the first year of life and presents as microcephaly, intellectual disability, epilepsy, severe developmental delay, speech impairment, gait ataxia, and a characteristic behavior with an inappropriate happy demeanor and frequent laughing. Angelman syndrome is a well-known disorder of genomic imprinting and is caused by loss of expression of the UBE3A gene on the maternally inherited chromosome 15. Children with Angelman most often have a large deletion of 15q11.2-q13, paternal uniparental disomy, or pathogenic sequence changes in UBE3A. In very rare instances, a defect of an imprinting center in 15q11.2 is the pathogenic cause.

A range of neurodevelopmental disorders are included in the differential diagnosis for Rett and Angelman syndromes. This spectrum includes Rett, atypical Rett, congenital Rett, Angelman, Angelman-like, Pitt-Hopkins, Mowat-Wilson, West, Ohtahara, Kleefstra, adenylosuccinate lyase deficiency, NGLY1 deficiency, and Koolen-DeVries syndromes. These syndromic disorders typically present with seizures, developmental delay, speech and language delays, intellectual disability, and variable congenital anomalies. A summary of the specific clinical features of some of these syndromes is provided in the table below as examples.

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
adenylosuccinate lyase deficiency Intellectual disability, autism, epilepsy, hypotonia, microcephaly
alpha-thalassemia X-linked intellectual disability (ATRX) syndrome Distinctive facial features, severe development delay, genital anomalies, intellectual disability, abnormal hemoglobin H production
Glass syndrome Intellectual disability, cleft or high-arched palate, distinctive facial features, microcephaly, growth retardation, joint laxity, seizures, behavioral issues
succinic semialdehyde dehydrogenase (SSADH) deficiency hypotonia, ataxia, hyporeflexia, intellectual disability, sleep disorders, hyperactivity, behavior problems, anxiety, obsessive-compulsive disorder, seizures

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.

Clinical conditionPercentage of clinical cases in which a pathogenic variant is expected
Rett/Atypical Rett syndromes MECP2: 95% of females with Rett syndrome cases and 75% of females with atypical Rett syndrome cases; CDKL5: 13% of atypical Rett syndrome cases; FOXG1: 1% of Rett syndrome cases; MBD5 and MEF2C are rare causes of Rett-like syndrome.
Angelman/Angelman-like syndromes* UBE3A: 90% of Angelman syndrome cases; SLC9A6: 6% of Angelman sydrome cases; MBD5: Rare cause of Angelman-like syndrome (Christianson syndrome) cases); MECP2: Rare cause of Angelman-like syndrome cases.
Pitt-Hopkins syndrome TCF4: 38% of Pitt-Hopkins syndrome cases.
Mowat-Wilson syndrome** ZEB2: 98% of Mowat-Wilson syndrome cases.
Koolen-DeVries syndrome (17q21.31 microdeletion syndrome) KANSL1: 100% of Koolen-DeVries syndrome cases.
adenylosuccinate lyase deficiency ADSL: 100% of adenylosuccinate lyase deficiency cases
alpha-thalassemia X-linked intellectual disability (ATRX) syndrome ATRX: 100% of ATRX syndrome cases.
Glass syndrome SATB2: 100% of Glass  syndrome
succinic semialdehyde dehydrogenase (SSADH) deficiency ALDH5A1: 100% of SSADH deficiency cases.

*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 disorders in the Rett/Angelman spectrum 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
  • adenylosuccinate lyase deficiency: rare, fewer than 100 cases reported
  • alpha-thalassemia X-linked intellectual disability (ATRX) syndrome: unknown
  • 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. Akaboshi, S, et al. Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency. Hum. Mutat. 2003; 22(6):442-50. PMID: 14635103
  3. 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
  4. Ardinger, HH, et al. Pitt-Hopkins Syndrome. 2012 Aug 30. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 22934316
  5. 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
  6. 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
  7. 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
  8. 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
  9. 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
  10. Christodoulou, J, Ho, G. MECP2-Related Disorders. 2001 Oct 03. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301670
  11. 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
  12. Dagli, AI, et al. Angelman Syndrome. 1998 Sep 15. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301323
  13. Fisher, RS, et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia. 2014; 55(4):475-82. PMID: 24730690
  14. 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
  15. 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
  16. 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
  17. 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
  18. 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
  19. Lossie, AC, et al. Distinct phenotypes distinguish the molecular classes of Angelman syndrome. J. Med. Genet. 2001; 38(12):834-45. PMID: 11748306
  20. 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
  21. Phelan, K, Rogers, RC. Phelan-McDermid Syndrome. 2005 May 11. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301377
  22. Schroer, RJ, et al. Natural history of Christianson syndrome. Am. J. Med. Genet. A. 2010; 152A(11):2775-83. PMID: 20949524
  23. Stevenson, RE. Alpha-Thalassemia X-Linked Intellectual Disability Syndrome. 2000 Jun 19. In: Pagon, RA, et al, editors. GeneReviews(®) (Internet). University of Washington, Seattle. PMID: 20301622
  24. 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
  25. 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
  26. 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
  27. 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
ADSL NM_000026.2
ALDH5A1 NM_001080.3
ATRX NM_000489.4
CDKL5 NM_003159.2
CNTNAP2 NM_014141.5
DYRK1A NM_001396.3
EHMT1 NM_024757.4
FOXG1 NM_005249.4
GABRD NM_000815.4
IQSEC2 NM_001111125.2
KANSL1* NM_001193466.1
MBD5 NM_018328.4
MECP2 NM_004992.3, NM_001110792.1
MEF2C NM_002397.4
NGLY1 NM_018297.3
NRXN1 NM_001135659.1
SATB2 NM_015265.3
SCN8A* NM_014191.3
SLC9A6 NM_006359.2, NM_001042537.1
STXBP1 NM_003165.3
TBL1XR1 NM_024665.4
TCF4 NM_001083962.1
UBE3A NM_130838.1
WDR45 NM_007075.3
ZEB2 NM_014795.3

KANSL1: Deletion/duplication analysis is not offered for exons 2-3.
SCN8A: Analysis includes exon 6 of NM_001330260.1.