MECP2-Related Disorders - Rett Syndrome Testing

Rett Syndrome (MECP2), Sequencing and Deletion/Duplication 0051614
Method: Sequencing/Multiplex Ligation-dependent Probe Amplification

Comprehensive test to confirm a clinical or suspected diagnosis of Rett syndrome or MECP2-related disorder

Determine cause of severe neonatal encephalopathy or intellectual disability in males

Rule out MECP2 variant in individuals with clinical features of Angelman syndrome who lack a molecular abnormality involving 15q11.2-13

Rett Syndrome (MECP2), Full Gene Sequencing 0051378
Method: Polymerase Chain Reaction/Sequencing

Acceptable initial test to confirm a clinical or suspected diagnosis of Rett syndrome or MECP2-related disorder

Determine cause of severe neonatal encephalopathy or intellectual disability in males

Rule out MECP2 variant in individuals with clinical features of Angelman syndrome who lack a molecular abnormality involving 15q11.2-13

Related Tests
CDKL5-Related Disorders (CDKL5) Sequencing and Deletion/Duplication 2004935
Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Useful for individuals with early-onset seizures and intellectual disability and negative MECP2 full-gene analysis

For test-specific information, see the CDKL5-Related Disorders Test Fact Sheet.

Familial Mutation, Targeted Sequencing 2001961
Method: Polymerase Chain Reaction/Sequencing

Recommended test for a known familial sequence variant previously identified in a family member.

A copy of the family member’s lab report documenting the familial variant is REQUIRED.

Consultation with a genetic counselor is advised.

MECP2-related disorders are a spectrum of disorders with varying severity, including Rett syndrome, MECP2 duplication syndrome, PPM-X syndrome (the mildest of the MECP2-related disorders), and MECP2 neonatal encephalopathy (the most severe of the MECP2-related disorders). In females, MECP2 disorders include classic and atypical Rett syndrome and intellectual disability. In males, MECP2 disorders include severe neonatal congenital encephalopathy, intellectual disability, and MECP2 duplication syndrome. (Matijevic, 2009) For more information, see the MECP2-Related Disorders – Classic or Atypical Rett Syndrome Consult topic. 

Testing Strategy

Consultation with a genetic counselor is recommended to determine the optimal MECP2 genetic testing strategy. The patient’s clinical phenotype also guides testing strategy. 

  • Consider MECP2 sequencing for:
    • Females with
      • A classic or atypical Rett syndrome phenotype
      • Nonspecific intellectual disability
      • Autism
      • Clinically suspected but molecularly unconfirmed Angelman syndrome
    • Males with
      • Unexplained neonatal encephalopathy
      • Nonspecific intellectual disability
      • A classic or atypical Rett syndrome phenotype
      • Manic-depressive psychosis, pyramidal signs, Parkinsonian and macroorchidism (PPM-X) syndrome
      • Clinically suspected but molecularly unconfirmed Angelman syndrome
  • Consider MECP2 deletion/duplication analysis for:
    • Females when suspicion for classic or atypical Rett syndrome remains despite a negative MECP2 sequencing result
    • Males with suspected MECP2 duplication syndrome

Disease Overview

Rett Syndrome

MECP2 Duplication Syndrome

  • Incidence:
    • 1-2% of males with neonatal encephalopathy or moderate to severe intellectual disability
    • >200 cases have been reported
  • Clinical phenotype
    • Males:
      • Variable intellectual disability in males, including developmental regression in some individuals
      • Hypotonia and feeding problems during infancy
      • Seizures in ~50% of cases
    • Females:
      • Asymptomatic or mild symptoms due to X-inactivation

MECP2 Severe Neonatal Encephalopathy

  • Incidence:
    • Rare; 20-30 cases reported
  • Clinical phenotype:
    • Affects males
    • Brain dysfunction, microcephaly, hypotonia, and seizures
    • Death usually occurs before age 2 due to respiratory failure

PPM-X Syndrome

  • Incidence:
    • Rare; prevalence unknown
  • Clinical phenotype
    • Males:
      • Psychotic disorders (commonly bipolar disorder)
      • Movement abnormalities (Parkinsonism)
      • Mild to severe intellectual disability and impaired language development
      • Microcephaly
      • Muscle spasticity
      • May have enlarged testes (macro-orchidism)
    • Females:
      • Mild intellectual disability or learning disability

Genetics

Gene

MECP2

Inheritance

  • X-linked dominant
  • 99.5% of cases are sporadic

Penetrance

  • Nearly 100% in females
  • Some females with a MECP2 variant may be asymptomatic due to skewed X-inactivation
  • Disruption of MECP2 in males is usually lethal

Variants

>350 known pathogenic variants 

  • ~95-97% of individuals with classic Rett syndrome have a pathogenic variant in MECP2
  • ~50%-70% of individuals with atypical Rett syndrome have a pathogenic variant in MECP2
  • Sequence variants
    • Majority of MECP2 sequence variants occur in exon 4
  • Deletions/duplications
    • Large deletions most commonly involve exon 3 and/or exon 4 of MECP2
    • Males with whole-gene duplications are clinically affected

Test Interpretation

Sensitivity/Specificity

  • Clinical sensitivity
    • Classic Rett syndrome:
      • Sequencing: ~80%  
      • Deletions/duplications: ~8-10%  
    • Atypical Rett syndrome:
      • Sequencing: ~40%  
      • Deletions/duplications: ~3% 
  • Analytical sensitivity
    • Sequencing: 99%
    • Deletions/duplications: 90%
  • Analytical specificity
    • Sequencing: 99%
    • Deletions/duplications: 98%

Results

Result Findings Interpretation

Positive

Pathogenic variant identified

Diagnosis confirmed

Negative

No pathogenic variant identified

Possibility of an MECP2-related disorder is decreased, but not excluded

Uncertain

Variant(s) of uncertain significance identified

Variant(s) may be disease-causing or benign

Limitations

  • Diagnostic errors may occur due to rare sequence variations or repeat element insertions
  • Breakpoints of large deletions/duplications and regulatory region and deep intronic variants are not detected
  • Single exon deletion/duplications may not be detected due to probe location
References 
  1. Matijevic T, Knezevic J, Slavica M, Pavelic J. Rett syndrome: from the gene to the disease. Eur Neurol. 2009; 61(1): 3-10. PubMed
  2. Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, Leonard H, Bailey ME, Schanen C, Zappella M, Renieri A, Huppke P, Percy AK, RettSearch Consortium. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010; 68(6): 944-50. PubMed
  3. Fukuda T, Yamashita Y, Nagamitsu S, Miyamoto K, Jin J, Ohmori I, Ohtsuka Y, Kuwajima K, Endo S, Iwai T, Yamagata H, Tabara Y, Miki T, Matsuishi T, Kondo I. Methyl-CpG binding protein 2 gene (MECP2) variations in Japanese patients with Rett syndrome: pathological mutations and polymorphisms. Brain Dev. 2005; 27(3): 211-7. PubMed
  4. Li M, Pan H, Bao X, Zhang Y, Wu X. MECP2 and CDKL5 gene mutation analysis in Chinese patients with Rett syndrome. J Hum Genet. 2007; 52(1): 38-47. PubMed
  5. Archer HL, Whatley SD, Evans JC, Ravine D, Huppke P, Kerr A, Bunyan D, Kerr B, Sweeney E, Davies SJ, Reardon W, Horn J, MacDermot KD, Smith RA, Magee A, Donaldson A, Crow Y, Hermon G, Miedzybrodzka Z, Cooper DN, Lazarou L, Butler R, Sampson J, Pilz DT, Laccone F, Clarke AJ. Gross rearrangements of the MECP2 gene are found in both classical and atypical Rett syndrome patients. J Med Genet. 2006; 43(5): 451-6. PubMed
  6. National Institutes of Health. MECP2 Gene. National Institutes of Health, U.S. National Library of Medicine. [Last Reviewed: Mar 2017; Accessed: Aug 2019]
  7. Percy AK, Lane JB, Childers J, Skinner S, Annese F, Barrish J, Caeg E, Glaze DG, MacLeod P. Rett syndrome: North American database. J Child Neurol. 2007; 22(12): 1338-41. PubMed

Last Update: August 2019