MECP2 Gene, Full Gene Analysis
Diagnosis of Rett syndrome or other MECP2-related disorders
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Methyl-CpG-binding protein 2 (MeCP2) is a transcriptional repressor protein encoded by the MECP2 gene located on the X chromosome. Genetic mutations in MECP2 alter the expression of targeted genes and can be associated with variable phenotypes in females including classic Rett syndrome, variant or atypical Rett syndrome, mild mental retardation, and asymptomatic carriers. Males with MECP2 mutations can present with variable phenotypes as well. The variability in males can, in part, be attributed to the type of MECP2 mutation present; point mutations are typically associated with severe neonatal encephalopathy and gene duplications are associated with MECP2 duplication syndrome. Full MECP2 gene analysis via sequencing and large duplication/deletion studies has been useful in identifying germline mutations in individuals with these clinical presentations.
Rett syndrome is an X-linked, panethnic condition with an incidence of approximately 1/8,500 to 1/15,000 females. Disease course typically begins after 6 to 18 months of apparently normal development with rapid regression in language and motor skills. A hallmark feature of this condition is repetitive, stereotyped hand movements, sometimes described as hand-wringing. Clinical criteria have been established for diagnosis of classic and atypical or variant Rett syndrome. Greater than 88% of females with a clinical diagnosis of classic Rett syndrome demonstrate a mutation by this test. The detection rate is approximately 43% for females with a clinical diagnosis of atypical or variant Rett syndrome. For individuals in which there is clinical suspicion for Rett syndrome but clinical criteria are not met, the detection rate is lower given the phenotypic overlap with other conditions (eg, Angelman syndrome).
Nonrandom X chromosome inactivation, resulting in phenotypic variability within families, has been reported in females with MECP2 mutations. Although 99.5% of mutations associated with Rett syndrome are de novo, asymptomatic or very mildly affected carrier mothers of classically affected daughters have been reported. Genetic counseling should be provided with this, and the possibility of germline or somatic mosaicism, in mind.
MECP2 Duplication Syndrome
Although MECP2 mutations are reported in males, these males typically do not present with classic Rett syndrome unless an abnormal karyotype (ie, 47,XXY) or somatic mosaicism is also present. More commonly, MECP2 mutations have been reported in karyotypically normal males presenting with neonatal encephalopathy and mental retardation syndromes. MECP2 duplication syndrome is an increasingly reported severe mental retardation syndrome characterized by infantile hypotonia, absence of speech, and progressive spasticity. Seizures and recurrent respiratory infections are commonly reported as well. These MECP2 gene duplications vary in size from 0.3 Mb to 2.3 Mb. Although chromosome analysis can identify some larger duplications, other methods such as multiplex ligation-dependent probe amplification (MLPA) can identify essentially all MECP2 gene duplications. Males with non-gene duplication type mutations can present with other mental retardation syndromes (ie, Angelman-like syndrome) or neonatal encephalopathy and early death.
To date, all males found to have an MECP2 duplication are clinically affected and have inherited the duplication from their asymptomatic mothers. Therefore, mothers of sons with MECP2 duplication syndrome are thought to be obligate carriers whose male offspring have a 50% risk of being affected.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
An interpretive report will be provided.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
A small percentage of individuals who are carriers or have a diagnosis of a MECP2-related disorder may have a mutation that is not identified by this method (eg, promoter mutations, deep intronic alterations). The absence of a mutation(s), therefore, does not eliminate the possibility of positive carrier status or the diagnosis of a MECP2-related disorder. For carrier testing, it is important to first document the presence of a MECP2 gene mutation in an affected family member.
In some cases, DNA alterations of undetermined significance may be identified.
Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given to us is inaccurate or incomplete.
In addition to disease-related probes, the MLPA technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.
Phenotypic overlap exists between MECP2-related conditions and several conditions not associated with MECP2 mutations. This assay will not detect alterations in other genes or chromosomal rearrangements that could result in a similar phenotype.
Clinical Reference Provides recommendations for further in-depth reading of a clinical nature
1. Moretti P, Zoghbi HY: MeCP2 dysfunction in Rett syndrome and related disorders. Curr Opin Genet Dev 2006;6(3):276-281.
2. Shahbazian MD, Zoghbi HY: Molecular genetics of Rett syndrome and clinical spectrum of MECP2 mutations. Curr Opin Genet Dev 2001;14:171-176.
3. Van Esch H, Bauters M, Ignatius J, et al: Duplication of the MECP2 region is a frequent cause of severe mental retardation and progressive neurological symptoms in males. Am J Hum Genet 2005;77:442-453.
4. Hagberg B, Hanefeld F, Percy A, Skjedal O: An update on clinically applicable diagnostic criteria in Rett syndrome. European Journal of Paediatric Neurology 2002:6:293-297.
5. Laurvick CL, de Klerk N, Bower C, et al: Rett syndrome in Australia: A review of the epidemiology. The Journal of Pediatrics 2006:148:347-352.