Coverage Policy Manual
Policy #: 2012043
Category: Laboratory
Initiated: August 2012
Last Review: June 2023
  Genetic Test: Rett Syndrome
Description:
Rett syndrome (RTT), a neurodevelopmental disorder, is usually caused by pathogenic variants in the methyl-CpG-binding protein 2 (MECP2) gene. Genetic testing is available to determine whether a pathogenic mutation exists in RTT-associated genes (e.g., MECP2, FOXG1, or CDLK5) in an individual with clinical features of RTT, or a individual’s family member.
 
Background
Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting girls with an incidence of 1:10,000 female births and a prevalence of 7.1 per 100,000 females, making it one of the most common genetic causes of intellectual disability in girls (Williamson, 2006; Petriti, 2023). RTT is characterized by apparently normal development for the first 6-18 months of life, followed by regression of intellectual functioning, acquired fine and gross motor skills, and social skills. Purposeful use of the hands is replaced by repetitive stereotyped hand movements, sometimes described as hand-wringing (Williamson, 2006). Other clinical manifestations include seizures, disturbed breathing patterns with hyperventilation and periodic apnea, scoliosis, growth retardation, and gait apraxia (Lotan, 2006).  
 
There is wide variability in the rate of progression and severity of the disease. In addition to the typical (or classic) form of RTT, there are a number of recognized atypical variants. Three distinct atypical variants have been described: preserved speech, early seizure, and congenital variants. RTT occurring in males is also considered a variant type and is associated with somatic mosaicism or Klinefelter (XXY) syndrome. A small number of RTT cases in males arising from the MECP2 exon 1 variant have been reported. Diagnostic criteria for typical (or classic) RTT and atypical (or variant) RTT have been established (Williamson, 2006; Lotan, 2006; Neul, 2010). For typical RTT, a period of regression followed by recovery or stabilization and fulfillment of all the main criteria are required to meet the diagnostic criteria for classic RTT. For atypical RTT, a period of regression followed by recovery or stabilization, at least 2 of the 4 main criteria, plus 5 of 11 supportive are required to meet the diagnostic criteria of variant RTT.
 
Treatment of Rett syndrome
There are currently no specific treatments that halt or reverse the progression of the disease, and there are no known medical interventions that will change the outcome of patients with RTT. Management is mainly symptomatic and individualized, focusing on optimizing each patient’s abilities (Williamson, 2006). A multidisciplinary approach is usually applied, with specialist input from dietitians, physical therapists, occupational therapists, speech therapists and music therapists. Regular monitoring for scoliosis (seen in about 87% of patients by age 25 years) and possible heart abnormalities, particularly cardiac conduction abnormalities, may be recommended. Spasticity can have a major impact on mobility; physical therapy and hydrotherapy may prolong mobility. Occupational therapy can help children develop communication strategies and skills needed for performing self-directed activities (such as dressing, feeding, and practicing arts and crafts).
 
Pharmacological approaches to managing problems associated with RTT include melatonin for sleep disturbances, several agents for the control of breathing disturbances; seizures; and stereotypic movements. RTT patients have an increased risk of life-threatening arrhythmias associated with a prolonged QT interval, and avoidance of a number of drugs is recommended, including prokinetic agents, antipsychotics, tricyclic antidepressants, antiarrhythmics, anesthetic agents and certain antibiotics.
 
In a mouse model of RTT, genetic manipulation of the MECP2 gene has demonstrated reversibility of the genetic defect (Guy, 2007; Robinson, 2012).
 
Genetics of Rett syndrome
RTT is an X-linked dominant genetic disorder. Pathogenic variants in MECP2 gene, which is thought to control expression of several genes including some involved in brain development, were first reported in 1999. Subsequent screening has shown that over 80% of individuals with classical RTT have pathogenic mutations in the MECP2 gene. More than 200 pathogenic variants in MECP2 have been associated with RTT (Suter, 2014) However, 8 of the most commonly occurring missense and nonsense variants account for almost 70% of all cases; small C-terminal deletions account for approximately10% and large deletions 8-10% (Cuddapah, 2014). MECP2 variant type is associated with severe X-linked intellectual disability with progressive spasticity, no or poor speech acquisition, and acquired microcephaly. In addition, the pattern of X-chromosome inactivation influences the severity of the clinical disease in females (Archer, 2007; Weaving, 2003).
 
Because the spectrum of clinical phenotypes is broad, to facilitate genotype-phenotype correlation analyses, the International Rett Syndrome Association has established a locus-specific MECP2 variation database (RettBASE) and a phenotype database (InterRett).
 
Approximately 99.5% of cases of RTT are sporadic, resulting from a de novo variant, which arises almost exclusively on the paternally derived X chromosome. The remaining 0.5% of cases, are familial and usually explained by germline mosaicism or favorably skewed X-chromosome inactivation in the carrier mother that results in her being unaffected or only slightly affected (mild intellectual disability). In the case of a carrier mother, the recurrence risk of RTT is 50%. If a variant is not identified in leukocytes of the mother, the risk to a sibling of the proband is below 0.5% (since germline mosaicism in either parent cannot be excluded).
 
The identification of a variant in MECP2 does not necessarily equate to a diagnosis of RTT. Rare cases of MECP2 variants have also been reported in other clinical phenotypes, including individuals with an Angelman-like picture, nonsyndromic X-linked intellectual disability, PPM-X syndrome (an X-linked genetic disorder characterized by psychotic disorders [most commonly bipolar disorder], parkinsonism, and intellectual disability), autism and neonatal encephalopathy (Williamson, 2006; Suter, 2014; Liyanage, 2014). Recent studies have revealed that different classes of genetic variants in MECP2 result in variable clinical phenotypes and overlap with other neurodevelopmental disorders (Zahorakova, 2016; Sheikh, 2016; Schonewolf-Greulich, 2016).
 
A proportion of patients with a clinical diagnosis of RTT do not appear to have pathologic variants in the MECP2 gene. Two other genes, CDKL5 and FOXG1 have been shown to be associated with atypical variants.
 
Regulatory Status
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Genetic testing for Rett syndrome is available under the auspices of the CLIA. Laboratories that offer laboratory-developed tests must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.
Policy/
Coverage:
Effective June 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Mutation testing for Rett syndrome- associated genes (MECP2, FOXG1 or CDKL5) to confirm a diagnosis of Rett syndrome meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes  in a child with developmental delay and signs/symptoms of Rett syndrome, when there is uncertainty in the clinical diagnosis.
 
Targeted genetic testing for a known familial Rett syndrome-associated variant to determine carrier status of a mother or a sister of an individual with Rett syndrome meets member benefit certificate primary coverage criteria and is covered.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
All other indications for genetic testing for Rett syndrome-associated genes (eg, MECP2, FOXG1, or CDKL5), including carrier testing (preconception or prenatal), and testing of asymptomatic family members to determine future risk of disease is a contract exclusion in most member benefit certificates of coverage and does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For member with contracts without primary coverage criteria and/or the specific contract exclusion, all other indications for genetic testing for Rett syndrome-associated genes (eg, MECP2, FOXG1, or CDKL5), including carrier testing (preconception or prenatal), and testing of asymptomatic family members to determine future risk of disease are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates.
 
Effective Prior to June 2018
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Mutation testing for Rett syndrome- associated genes (MECP2, FOXG1 or CDKL5) to confirm a diagnosis of Rett syndrome meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes  in a child with developmental delay and signs/symptoms of Rett syndrome, when there is uncertainty in the clinical diagnosis.
 
Targeted genetic testing for a known familial Rett syndrome-associated variant to determine carrier status of a mother or a sister of an individual with Rett syndrome meets member benefit certificate primary coverage criteria and is covered.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
All other indications for genetic testing for Rett syndrome-associated genes (eg, MECP2, FOXG1, or CDKL5), including carrier testing (preconception or prenatal), and testing of asymptomatic family members to determine future risk of disease is a contract exclusion in most member benefit certificates of coverage and does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For member with contracts without primary coverage criteria and/or the specific contract exclusion, all other indications for genetic testing for Rett syndrome-associated genes (eg, MECP2, FOXG1, or CDKL5), including carrier testing (preconception or prenatal), and testing of asymptomatic family members to determine future risk of disease are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates.
 
Effective Prior to September 2017
 
Mutation testing for Rett syndrome to confirm a diagnosis of Rett syndrome meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes  in a female child with developmental delay and signs/symptoms of Rett syndrome, when there is uncertainty in the clinical diagnosis.
 
All other indications for mutation testing for Rett syndrome, including prenatal screening and testing of family members, do not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For member with contracts without primary coverage criteria, all other indications for mutation testing for Rett syndrome, including prenatal screening and testing of family members, are considered investigational. Investigational services are specific contract exclusions in most member benefit certificates.
 
Rationale:
This policy was created in 2012 and is based on a search of the MEDLINE database through March 2012. Literature that describes the analytic validity, clinical validity, and clinical utility of genetic testing for RTT was sought.
 
Analytic validity (the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent)
 
The test is generally done as full gene sequencing of the MECP2 gene to diagnose atypical or classic Rett syndrome (RTT) and as multiplex ligation probe amplification (MLPA) for duplication/deletion analysis. Familial mutation testing may be done with targeted sequencing. CDKL5 sequencing may be done for atypical RTT.
 
According to a large reference laboratory, MECP2 testing for RTT has an analytical sensitivity for sequencing of 99% and for MLPA 90%; analytic specificity is 99% for sequencing and for MLPA 98%.
 
Clinical validity (the diagnostic performance of the test [sensitivity, specificity, positive and negative predictive values] in detecting clinical disease)
 
Huppke and colleagues analyzed the MECP2 gene in 31 female patients diagnosed clinically with RTT (Huppke, 2000). Sequencing revealed mutations in 24 of the 31 patients (77%). Of the 7 patients in whom no mutations were found, 5 fulfilled the criteria for classical RTT. In this study, 17 different mutations were detected, 11 of which had not been previously described. Several females carrying the same mutation displayed different phenotypes, suggesting that factors other than the type or position of mutations influence the severity of RTT.
 
Cheadle and colleagues analyzed mutations in 48 females with classical sporadic RTT, 7 families with possible familial RTT, and 5 sporadic females with features suggestive, but not diagnostic, of RTT (Cheadle,2000). The entire MECP2 gene was sequenced in all cases. Mutations were identified in 44/55 (80%) of unrelated classical sporadic and familial RTT patients. Only 1 out of 5 (20%) sporadic cases with suggestive but non-diagnostic features of RTT had mutations identified. Twenty-one different mutations were identified (12 missense, 4 nonsense, and 5 frame-shift mutations); 14 of the mutations identified were novel. Significantly milder disease was noted in patients carrying missense mutations as compared to those with truncating mutations.
 
Lotan and colleagues summarized 6 articles that attempted to disclose a genotype-phenotype correlation, which included the 2 studies outlined above (Lotan, 2006). The authors found that these studies have yielded inconsistent results and that further controlled studies are needed before valid conclusions can be drawn about the effect of mutation type on phenotypic expression.
 
Evidence from several small studies indicates that the clinical sensitivity of genetic testing for classical RTT is reasonably high, in the range of 75-80%. However, the sensitivity may be lower when classic features of RTT are not present. The clinical specificity is unknown but is also likely to be high as only rare cases of MECP2 mutations have been reported in other clinical phenotypes, including individuals with an Angelman-like picture, nonsyndromic X-linked mental retardation, PPM-X syndrome, autism and neonatal encephalopathy.
 
Clinical utility (how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes)
 
The clinical utility of genetic testing can be considered in the following clinical situations: 1) individuals with suspected RTT, 2) family members of individuals with RTT, and 3) prenatal testing for mothers with a previous RTT child. These situations will be discussed separately below.
 
Individuals with suspected RTT. The clinical utility for these patients depends on the ability of genetic testing to make a definitive diagnosis and for that diagnosis to lead to management changes that improve outcomes. No studies were identified that described how a molecular diagnosis of RTT changed patient management. Therefore there is no direct evidence for the clinical utility of genetic testing in these patients.
 
There is no specific treatment for RTT, so that making a definitive diagnosis will not lead to treatment that alters the natural history of the disorder. There are several potential ways in which adjunctive management might be changed following genetic testing after confirmation of the diagnosis:
 
    • Further diagnostic testing may be avoided
    • Referral to a specialist(s) may be made
    • Heightened surveillance for Rett-associated clinical manifestations, such as scoliosis or cardiac arrhythmias may be performed
    • More appropriate tailoring of ancillary treatments such as occupational therapy may be possible
 
Family members. Genetic testing can be done in sisters of girls with RTT who have an identified MECP2 mutation to determine if they are asymptomatic carriers of the disorder. However, this is an extremely rare possibility since the disorder is nearly always sporadic. Testing of family members of individuals with RTT will therefore result in an extremely low yield.
 
Prenatal screening.
It may be appropriate to offer prenatal diagnosis to a couple who have had a child with RTT or mental retardation due to a MECP2 mutation. Since the disorder occurs spontaneously in most affected individuals, however, the risk of a family having a second child with the disorder is less than 1 percent, except in the rare situation where the mother carries the mutation (Amir, 2005). Therefore, for mothers without the Rett phenotype, it is extremely unlikely that prenatal testing will identify cases of RTT.
 
The clinical utility of genetic testing for RTT has not been established in the literature, however, genetic testing can confirm the diagnosis in patients with clinical signs and symptoms of Rett syndrome, and management changes may result. In addition, a definitive diagnosis can avoid further testing for other possible diagnoses. For testing family members and for prenatal testing, the clinical utility is lacking since the yield of testing in those situations is extremely low.
 
Summary
MECP2 mutations are found in the majority of patients with RTT, particularly those who present with classical clinical features of RTT. The diagnostic accuracy of mutation testing for RTT cannot be determined with absolute certainty given the lack of a true gold standard for the diagnosis of RTT, but appears to have high sensitivity and specificity.
 
Testing for MECP2 mutations has clinical utility in certain clinical scenarios. The diagnosis of RTT is considered to be a clinical one, characterized by a specific developmental profile that should meet certain clinical diagnostic criteria. Certain atypical variants of RTT may be more difficult to diagnose clinically, and MECP2 mutation testing may be useful in confirming or excluding the diagnosis of RTT. Although there is no effective treatment for RTT, and management is mainly supportive, a definitive diagnosis can end a diagnostic workup for other possible diagnoses and may alter some aspects of management (e.g., determining whether or not to advise avoidance of medications that can prolong QT interval).
 
Testing of family members and prenatal testing in a couple who have had a child with RTT or mental retardation due to a MECP2 mutation is not likely to improve outcomes. The risk of a family having a second child with the disorder is less than 1 percent, except in the rare situation where the mother carries the mutation, and the impact on decision making on health outcomes is uncertain.
 
Practice Guidelines and Position Statements
A quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society issued an evidence report on the genetic and metabolic testing of children with global developmental delay (Michelson, 2011). The American Academy of Neurology recommends considering MECP2 mutation testing for all girls with unexplained moderate to severe developmental delay.
 
The American Academy of Pediatrics recommends MECP2 testing to confirm a diagnosis of suspected Rett syndrome, especially when the diagnosis isn’t clear from symptoms alone.
 
Medical organizations have not yet given recommendations on when to use CDKL5 testing, however, it has been suggested that patients who are negative for MEPC2 mutations and who have a strong clinical diagnosis of RTT, particularly if there are early onset seizures, should be considered for further screening of the CDKL5 gene (Williamson, 2006).
 
2016 Update
A literature search conducted through June  2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
 
A literature search was conducted using the MEDLINE database through July 2017. The following is a summary of the key identified literature.
 
Halbach et al (2016) analyzed a cohort from a group of 132 female patients between 2 and 43 years of age with well-defined RTT with extended clinical, molecular, and neurophysiological assessments (Halbach, 2016). Genotype-phenotype analyses of clinical features and cardiorespiratory data were performed after grouping variants by the same type and localization or having the same putative biologic effect on the MeCP2 protein, and subsequently on 8 single recurrent pathogenic variants. A less severe phenotype was seen in females with C-terminal segment of MECP2 (p.R133C and p.R294X variants). Autonomic disturbances were present in all females and not restricted to nor influenced by 1 specific group or any single recurrent pathogenic variant. The objective information from noninvasive neurophysiological evaluation of the disturbed central autonomic control is of great importance organizing the lifelong care for females with RTT. The study concluded that further research is needed to provide insights into the pathogenesis of autonomic dysfunction, and to develop evidence-based management in RTT.
 
Pidock et al (2016) identified 96 RTT patients with pathogenic variants in the MECP2 gene (Pidcock, 2016). Among 11 pathogenic variant groups, a statistically significant group effect of variant type was observed for selfcare, upper-extremity function, and mobility on standardized measures administered by occupational and physical therapists. Patients with R133C and uncommon variants tended to perform best on upper extremity and self-care items, whereas patients with R133C, R306C, and R294X variants had the highest scores on the mobility items. The worst performers on upper-extremity and self-care items were patients with large deletions (R255X, R168X, and T158M variants). The lowest scores for mobility were found in patients with T158M, R255X, R168X, and R270X variants. On categorical variables as reported by parents at the time of initial evaluation, patients with R133C and R294X variants were most likely to have hand use; those with R133C, R294X, R306C, and small deletions were most likely to be ambulatory; and those with the R133C variant were most likely to be verbal.
 
Sajan et al (2017) analyzed 22 RTT patients without apparent MECP2, CDKL5, and FOXG1 pathogenic variants were subjected to both whole-exome sequencing and single-nucleotide variant array-based copy-number variant analyses (Sajan, 2017). Three patients had MECP2 variants initially missed by clinical testing. Of the remaining 19, 17 (89.5%) had 29 other likely pathogenic intragenic variants and/or copy number variants (10 patients had ≥2). Thirteen patients had variants in a gene/region previously reported in other neurodevelopmental disorders, thereby providing a potential diagnostic yield of 68.4%. The genetic etiology of RTT without MECP2, CDKL5, and FOXG1 variants is heterogeneous, overlaps with other neurodevelopmental disorders, and is complicated by a high variant burden. Dysregulation of chromatin structure and abnormal excitatory synaptic signaling may form 2 common pathologic bases of RTT.
 
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2019. No new literature was identified that would prompt a change in the coverage statement.
 
2020 Update
A literature search was conducted through May 2020.  There was no new information identified that would prompt a change in the coverage statement.  
 
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2021. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
In 2020, the AAP published Clinical Report Guidance on the identification, evaluation, and management of children with autism spectrum disorder which stated that "if patient is a girl, consider evaluation for Rett syndrome, MECP2 testing" (Hyman, 2020).
 
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2022. No new literature was identified that would prompt a change in the coverage statement.
 
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through May 2023. No new literature was identified that would prompt a change in the coverage statement.
CPT/HCPCS:
0234UMECP2 (methyl CpG binding protein 2) (eg, Rett syndrome), full gene analysis, including small sequence changes in exonic and intronic regions, deletions, duplications, mobile element insertions, and variants in non uniquely mappable regions
81302MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; full sequence analysis
81303MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; known familial variant
81304MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; duplication/deletion variants
References: Amir RE, Sutton VR, Van den Veyver IB.(2005) Newborn screening and prenatal diagnosis for Rett syndrome: implications for therapy. J Child Neurol 2005; 20(9):779-83.

Archer H, Evans J, Leonard H, et al.(2007) Correlation between clinical severity in patients with Rett syndrome with a p.R168X or p.T158M MECP2 mutation, and the direction and degree of skewing of X-chromosome inactivation. J Med Genet. Feb 2007; 44(2): 148-52. PMID 16905679

Cheadle JP, Gill H, Fleming N et al.(2000) Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Human molecular genetics 2000; 9(7):1119-29.

Cuddapah VA, Pillai RB, Shekar KV, et al.(2014) Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet. Mar 2014; 51(3): 152-8. PMID 24399845

Guy J, Gan J, Selfridge J, et al.(2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science. Feb 23 2007; 315(5815): 1143-7. PMID 17289941

Halbach N, Smeets EE, Julu P, et al.(2016) Neurophysiology versus clinical genetics in Rett syndrome: A multicenter study. Am J Med Genet A. Sep 2016;170(9):2301-2309. PMID 27354166

Huppke P, Laccone F, Kramer N et al.(2000) Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet 2000; 9(9):1369-75.

Hyman SL, Levy SE, Myers SM, et al.(2020) Identification, Evaluation, and Management of Children With Autism Spectrum Disorder. Pediatrics. Jan 2020; 145(1). PMID 31843864

Liyanage VR, Rastegar M.(2014) Rett syndrome and MeCP2. Neuromolecular Med. Jun 2014; 16(2): 231-64. PMID 24615633

Lotan M, Ben-Zeev B.(2006) Rett syndrome. A review with emphasis on clinical characteristics and intervention. TheScientificWorldJournal 2006; 6:1517-41.

Michelson DJ, Shevell MI, Sherr EH et al.(2011) Evidence report: Genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2011; 77(17):1629-35.

Neul JL, Kaufmann WE, Glaze DG, et al.(2010) Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. Dec 2010; 68(6): 944-50. PMID 21154482

Petriti U, Dudman DC, Scosyrev E, et al.(2023) Global prevalence of Rett syndrome: systematic review and meta-analysis. Syst Rev. Jan 16 2023; 12(1): 5. PMID 36642718

Pidcock FS, Salorio C, Bibat G, et al.(2016) Functional outcomes in Rett syndrome. Brain Dev. Jan 2016;38(1):76-81. PMID 26175308

Robinson L, Guy J, McKay L, et al.(2012) Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome. Brain. Sep 2012; 135(Pt 9): 2699-710. PMID 22525157

Sajan SA, Jhangiani SN, Muzny DM, et al.(2017) Enrichment of mutations in chromatin regulators in people with Rett syndrome lacking mutations in MECP2. Genet Med. Jan 2017;19(1):13-19. PMID 27171548

Schonewolf-Greulich B, Tejada MI, Stephens K, et al.(2016) The MECP2 variant c.925C>T (p.Arg309Trp) causes intellectual disability in both males and females without classic features of Rett syndrome. Clin Genet. Clin Genet. Jun 2016;89(6):733-738. PMID 26936630

Sheikh TI, Ausio J, Faghfoury H, et al.(2016) From function to phenotype: impaired DNA Binding and clustering correlates with clinical severity in males with missense mutations in MECP2. Sci Rep. Dec 08 2016;6:38590. PMID 27929079

Suter B, Treadwell-Deering D, Zoghbi HY, et al.(2014) Brief report: MECP2 mutations in people without Rett syndrome. J Autism Dev Disord. Mar 2014; 44(3): 703-11. PMID 23921973

Weaving LS, Williamson SL, Bennetts B, et al.(2003) Effects of MECP2 mutation type, location and X-inactivation in modulating Rett syndrome phenotype. Am J Med Genet A. Apr 15 2003; 118A(2): 103-14. PMID 12655490

Williamson SL, Christodoulou J.(2006) Rett syndrome: new clinical and molecular insights. Eur J Hum Genet 2006; 14(8):896-903.

Zahorakova D, Lelkova P, Gregor V, et al.(2016) MECP2 mutations in Czech patients with Rett syndrome and Rett-like phenotypes: novel mutations, genotype-phenotype correlations and validation of high-resolution melting analysis for mutation scanning. J Hum Genet. Jul 2016;61(7):617-625. PMID 26984561
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