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, and intellectual disability and death typically occur before 2 years of age. Rett syndrome usually occurs as the result of a de novo variant 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-related 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.
Quick Answers for Clinicians
The diagnosis of Rett syndrome is based on clinical findings, including primary criteria (eg, loss of acquired purposeful hand skills and replacement with stereotypic hand movements) and supportive criteria (eg, 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.
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.
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.
Testing for CDKL5 or FOXG1 variants 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 that result 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 with equal frequency in males and females.
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
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-related disorder based on clinical presentation. In males, either MECP2 sequencing or deletion/duplication may be appropriate to confirm a suspected MECP2-related disorder, depending on clinical presentation.
CDKL5 and FOXG1 Testing
If MECP2 sequencing and/or deletion/duplication analysis is normal, testing for CDKL5 and FOXG1 gene variants should be considered. Although variants in CDKL5 and FOXG1 result in some clinical features that overlap with those of Rett syndrome, CDKL5 and FOXG1 pathogenic variants are associated with distinct clinical characteristics, suggesting that these are distinct disorders. Unlike MECP2 or CDKL5 variants, FOXG1 variants present with equal frequency in males and females.
Familial Variant Testing
Families with a known pathogenic variant may benefit from targeted testing for the familial variant.
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 that child has an identified pathogenic MECP2 variant. If the mother has the same pathogenic variant, the risk for the MECP2 variant in future 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, given that 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 Laboratory Tests
Useful test when there is a previously identified pathogenic sequencing variant; requires a copy of the relative’s lab report
Useful test when there is a previously identified pathogenic deletion/duplication variant; a copy of a relative’s lab report is REQUIRED
Pini G, Bigoni S, Congiu L, et al. Rett syndrome: a wide clinical and autonomic picture. Orphanet J Rare Dis. 2016;11(1):132.
Reichow B, George-Puskar A, Lutz T, et al. Brief report: systematic review of Rett syndrome in males. J Autism Dev Disord. 2015;45(10):3377-3383.
Neul JL, Kaufmann WE, Glaze DG, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944-950.
National Institutes of Health, U.S. National Library of Medicine. Genetics Home Reference: MECP2 duplication syndrome. [Published: Jun 2020; Accessed: Jun 2020]
National Organization for Rare Disorders. Rare Disease Database: MECP2 duplication syndrome. [Last update: 2017; Accessed: Jun 2020]