MECP2-Related Disorders - Classic or Atypical Rett Syndrome

MECP2-related disorders include classic Rett syndrome, atypical (or variant) Rett syndrome, and mild learning disabilities. Classic Rett syndrome is a rare, severe, X-linked neurodevelopmental disorder that most frequently affects females. It is characterized by normal development in the first 6-18 months of life, followed by regression of language and motor skills. Other features include stereotypic hand movements, intellectual disability, autistic characteristics, microcephaly, and seizures. In males, the disease presents as MECP2-related severe neonatal encephalopathy, with intellectual disability and death typically occurring before 2 years of age. Rett syndrome usually occurs as the result of a de novo mutation in the MECP2 gene, although inherited forms do exist. A rare neuropsychiatric phenotype that results from MECP2 duplications has also been documented. The clinical severity of MECP2 disorders is influenced by the specific MECP2 variant, and in females, the pattern of X inactivation. MECP2 genetic testing is used to confirm a clinical diagnosis and to determine recurrence risk; however, a negative molecular result does not exclude a diagnosis of classic Rett syndrome.

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Clinical Overview

Quick Answers

How is Rett syndrome diagnosed?

The diagnosis of Rett syndrome is based on clinical findings, including main criteria such as loss of acquired purposeful hand skills and replacement with stereotypic hand movements, and supportive criteria such as inappropriate laughter or screaming. Genetic testing is used to confirm a clinical diagnosis of Rett syndrome, although a pathogenic variant is not identified in all cases.

What are the optimal laboratory testing strategies for Rett syndrome and MECP2-related disorders in females and males?

In females, MECP2 sequencing can be used to detect the majority of pathogenic variants, followed by MECP2 deletion/duplication analysis if sequencing fails to reveal a causative variant. Other genes can also be tested if a pathogenic MECP2 variant is not identified. In males, the appropriate testing strategy depends on clinical presentation. Consultation with a genetic specialist is recommended to aid in optimal test selection for MECP2-related disorders. See the Rett Syndrome and MECP2-Related Disorders Test Fact Sheet for more information.

When should testing for MECP2 duplication syndrome be considered?

Testing for MECP2 duplication syndrome should be considered in males with severe intellectual disability, limited speech or a lack of speech, early-onset hypotonia, progressive spasticity, seizures, recurrent respiratory infections, ambulatory difficulties, or symptoms similar to classic Rett syndrome. Females who carry a duplication are usually asymptomatic, but may exhibit some behavioral and psychiatric symptoms. See the Rett Syndrome and MECP2-Related Disorders Test Fact Sheet for more information.

When should testing for CDKL5 or FOXG1 variants be considered?

Testing for CDKL5 or FOXG1 is appropriate when MECP2 testing has failed to reveal a causative variant for Rett syndrome or an MECP2-related disorder. Although variants of CDKL5 and FOXG1 have been associated with Rett syndrome, the symptoms resulting from pathogenic variants in these genes vary from the hallmarks of Rett syndrome. CDKL5 and FOXG1 pathogenic variants are associated with distinct clinical characteristics. It therefore has been suggested that these are clinically distinct disorders. Unlike MECP2 or CDKL5 variants, FOXG1 variants present equally frequently in males and females. See the CDKL5-Related Disorders Test Fact Sheet for more information about CDKL5-related disorders.

Testing for Genetic Syndromes Related to Developmental Delay, Intellectual Disability, and Autism Spectrum Disorder

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Indications for Testing

Genetic testing for Rett syndrome and MECP2-related disorders is used to:

Confirm a clinical diagnosis of Rett syndrome
Diagnose an MECP2-related disorder
Rule out an MECP2 variant in individuals with a clinically similar phenotype to an MECP2-related disorder (eg, in familial X-linked intellectual disability or in a patient with clinical features of Angelman syndrome, but no abnormality involving 15q11.2-13)
Determine risk of recurrence for parents of a child with a known MECP2 variant

Although genetic testing identifies a pathogenic variant in the majority of cases, failure to identify a pathogenic variant does not exclude a diagnosis of Rett syndrome or a related disorder.

Laboratory Testing

Diagnosis

MECP2 Testing

In females, MECP2 sequencing or full gene analysis (sequencing and deletion/duplication) detects the majority of pathogenic variants. MECP2 testing can be used to confirm the clinical diagnosis of Rett syndrome or to confirm clinical suspicion of an MECP2 disorder based on clinical presentation. In males, either MECP2 sequencing or deletion/duplication may be appropriate to confirm a suspected MECP2 disorder, depending on clinical presentation.

CDKL5 and FOXG1 Testing

If MECP2 sequencing and/or deletion/duplication analysis is normal, testing for the CDKL5 and FOXG1 genes should be considered. Although variants in CDKL5 and FOXG1 have some overlapping features with Rett syndrome, CDKL5 and FOXG1 pathogenic variants are associated with distinct clinical characteristics, suggesting that these are distinct disorders. FOXG1 variants, unlike MECP2 or CDKL5, present equally frequently in males and females.

Familial Variant Testing

Families with a known pathogenic variant may benefit from targeted testing for the familial variant.

Risk Assessment

Although the majority of MECP2 variants are de novo and have a low recurrence risk, the mother of an affected child should be offered testing if the affected individual has an identified pathogenic MECP2 variant. If the mother has the same pathogenic variant, the recurrence risk for offspring is 50%. However, regardless of the mother’s molecular genetic results, prenatal diagnosis should be offered to couples who already have a child with an identified MECP2 variant, as gonadal mosaicism is possible and may result in an affected future pregnancy. Carrier testing should be offered to all first-degree female relatives and to first-degree male relatives with neurodevelopmental abnormalities.

ARUP Lab Tests

MECP2 Testing

Preferred initial test to confirm a diagnosis of Rett syndrome in females; also used for males with a suspected MECP2-related disorder

For additional test information, refer to the Rett Syndrome and MECP2-Related Disorders Test Fact Sheet

Rett Syndrome (MECP2), Sequencing and Deletion/Duplication 0051614

Method: Sequencing/Multiplex Ligation-dependent Probe Amplification

Acceptable diagnostic test for females or males with a phenotype suggestive of classic or atypical Rett syndrome

For additional test information, refer to the Rett Syndrome and MECP2-Related Disorders Test Fact Sheet

Rett Syndrome (MECP2), Full Gene Sequencing 0051378

Method: Polymerase Chain Reaction/Sequencing

CDKL5 Testing

Most comprehensive test for a suspected CDKL5 disorder; may be useful for individuals with early-onset seizures and intellectual disability who had normal MECP2 full gene analysis

For additional test information, refer to the CDKL5-Related Disorders Test Fact Sheet

Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplification

Potentially useful test for individuals with early-onset seizures and intellectual disability who had normal MECP2 full gene analysis

Method: Polymerase Chain Reaction/Sequencing

Familial Variant Testing

Useful test when there is a previously identified pathogenic sequencing variant; requires a copy of the relative’s lab report

Familial Mutation, Targeted Sequencing 2001961

Method: Polymerase Chain Reaction/Sequencing

Medical Experts

Bayrak-Toydemir, Pinar, MD, PhD, FACMG, Medical Director, Molecular Genetics and Genomics, at ARUP Laboratories; Professor of Clinical Pathology, University of Utah

Jodah, Marcia, MS, LCGC, Senior Genetic Counselor, Molecular Genetics, at ARUP Laboratories

References

Pini G, Bigoni S, Congiu L, Romanelli AM, Scusa MF, Di Marco P, Benincasa A, Morescalchi P, Ferlini A, Bianchi F, Tropea D, Zappella M. Rett syndrome: a wide clinical and autonomic picture. Orphanet J Rare Dis. 2016; 11(1): 132. PubMed
Reichow B, George-Puskar A, Lutz T, Smith IC, Volkmar FR. Brief report: systematic review of Rett syndrome in males. J Autism Dev Disord. 2015; 45(10): 3377-83. PubMed
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
National Institutes of Health, US National Library of Medicine. MECP2 duplication syndrome. Genetics Home Reference. [Published: May 2019; Accessed: May 2019]
National Organization for Rare Disorders. Rare Disease Database: MECP2 Duplication Syndrome. [Published: 2017; Accessed: May 2019]

Additional Resources

Christodoulou J, Ho G. MECP2-Related Disorders. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, editors. GeneReviews, University of Washington, 1993-2019. Seattle, WA [Last updated: Jun 2012; Accessed: Jul 2019]

Echenne B, Roubertie A, Lugtenberg D, Kleefstra T, Hamel BC, Van Bokhoven H, Lacombe D, Philippe C, Jonveaux P, de Brouwer AP. Neurologic aspects of MECP2 gene duplication in male patients. Pediatr Neurol. 2009; 41(3): 187-91. PubMed

Mencarelli MA, Spanhol-Rosseto A, Artuso R, Rondinella D, De Filippis R, Bahi-Buisson N, Nectoux J, Rubinsztajn R, Bienvenu T, Moncla A, Chabrol B, Villard L, Krumina Z, Armstrong J, Roche A, Pineda M, Gak E, Mari F, Ariani F, Renieri A. Novel FOXG1 mutations associated with the congenital variant of Rett syndrome. J Med Genet. 2010; 47(1): 49-53. PubMed

Philippe C, Amsallem D, Francannet C, Lambert L, Saunier A, Verneau F, Jonveaux P. Phenotypic variability in Rett syndrome associated with FOXG1 mutations in females. J Med Genet. 2010; 47(1): 59-65. PubMed

Sanmann JN, Schaefer B, Buehler BA, Sanger WG. Algorithmic approach for methyl-CpG binding protein 2 (MECP2) gene testing in patients with neurodevelopmental disabilities. J Child Neurol. 2012; 27(3): 346-54. PubMed

Shoubridge C, Fullston T, Gécz J. ARX spectrum disorders: making inroads into the molecular pathology. Hum Mutat. 2010; 31(8): 889-900. PubMed

Testing Algorithms

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Read more about Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

Content Review:

May 2019

Last Update: June 2019

MECP2-Related Disorders - Classic or Atypical Rett Syndrome

Quick Answers

How is Rett syndrome diagnosed?

What are the optimal laboratory testing strategies for Rett syndrome and MECP2-related disorders in females and males?

When should testing for MECP2 duplication syndrome be considered?

When should testing for CDKL5 or FOXG1 variants be considered?

Testing for Genetic Syndromes Related to Developmental Delay, Intellectual Disability, and Autism Spectrum Disorder

Indications for Testing

Laboratory Testing

Diagnosis

MECP2 Testing

CDKL5 and FOXG1 Testing

Familial Variant Testing

Risk Assessment

ARUP Lab Tests

Medical Experts

References

Additional Resources

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

ARUP Laboratories

ARUP Websites

ARUP Consult


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MECP2-Related Disorders - Classic or Atypical Rett Syndrome

Quick Answers

How is Rett syndrome diagnosed?

What are the optimal laboratory testing strategies for Rett syndrome and MECP2-related disorders in females and males?

When should testing for MECP2 duplication syndrome be considered?

When should testing for CDKL5 or FOXG1 variants be considered?

Testing for Genetic Syndromes Related to Developmental Delay, Intellectual Disability, and Autism Spectrum Disorder

Indications for Testing

Laboratory Testing

Diagnosis

MECP2 Testing

CDKL5 and FOXG1 Testing

Familial Variant Testing

Risk Assessment

ARUP Lab Tests

Medical Experts

References

Additional Resources

Testing for Genetic Syndromes Related to Developmental Delay (DD), Intellectual Disability (ID), and Autism Spectrum Disorder (ASD)

ARUP Laboratories

ARUP Websites

ARUP Consult