|MP 2.04.81||Genetic Testing for Rett Syndrome|
|Original Policy Date
|Last Review Status/Date
Reviewed with literature search/9:2013
|Return to Medical Policy Index|
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Rett syndrome (RTT), a neurodevelopmental disorder, is usually caused by mutations in the MECP2 gene. Genetic testing is available to determine whether a pathogenic mutation exists in a patient with clinical features of Rett syndrome, or in a patient’s family member.
Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting girls with an incidence of 1:10,000 female births, making it one of the most common genetic causes of intellectual disability in girls. (1) RTT is characterized by apparent normal development for the first 6-18 months of life, followed by the loss of intellectual functioning, loss of acquired fine and gross motor skills and the ability to engage in social interaction. Purposeful use of the hands is replaced by repetitive stereotyped hand movements, sometimes described as hand-wringing. (1) Other clinical manifestations include seizures, disturbed breathing patterns with hyperventilation and periodic apnea, scoliosis, growth retardation and gait apraxia. (2)
There is wide variability in the rate of progression and severity of the disease. In addition to the classical form of RTT, there are a number of recognized atypical variants. Variants of RTT may appear with a severe or a milder form. The severe variant has no normal developmental period; individuals with a milder phenotype experience less dramatic regression and milder expression of the characteristics of classical RTT.
The diagnosis of RTT remains a clinical one, using diagnostic clinical criteria that have been established for the diagnosis of classic and variant Rett syndrome. (1-3)
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. (1) A multidisciplinary approach is usually used, with specialist input from dietitians, physiotherapists, occupational therapists, speech therapists and music therapists. Regular monitoring for scoliosis and possible heart abnormalities may be recommended. The development of scoliosis (seen in about 87% of patients by age 25 years) and the development of spasticity can have a major impact on mobility, and the development of effective communication strategies. Occupational therapy can help children develop skills needed for performing self-directed activities (such as dressing, feeding, and practicing arts and crafts), while physical therapy and hydrotherapy may prolong mobility.
Pharmacological approaches to managing problems associated with RTT include melatonin for sleep disturbances and 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 mutated MECP2 has demonstrated reversibility. (4, 5)
Genetics of Rett syndrome
RTT results from an X-linked dominant condition. Mutations in MECP2 (methyl-CpG-binding protein 2), which is thought to control expression of several genes including some involved in brain development, were first reported in 1999. Subsequent screening of RTT patients has shown that over 80% of classical RTT have pathogenic mutations in the MECP2 gene. More than 200 mutations in MECP2 have been described. However, 8 of the most commonly occurring missense and nonsense mutations account for almost 70% of all cases, small C-terminal deletions account for approximately 10%, and large deletions, 8–10%. (6) Whole duplications of the MECP2 gene have been associated with severe X-linked mental retardation 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.
As 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 mutation, which arise 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 mental retardation). In the case of a carrier mother, the recurrence risk of RTT is 50%. If a mutation 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 mutation in MECP2 does not necessarily equate to a diagnosis of RTT. Rare cases of MECP2 mutations have also been reported in other clinical phenotypes, including individuals with an Angelman-like picture, nonsyndromic X-linked mental retardation, PPM-X syndrome (an X-linked genetic disorder characterized by psychotic disorders [most commonly bipolar disorder], parkinsonism, and mental retardation), autism and neonatal encephalopathy. (1)
A proportion of patients with a clinical diagnosis of RTT do not appear to have mutations in the MECP2 gene. Two other genes, CDKL5 and FOXG1, have been shown to be associated with atypical variants.
No U.S. Food and Drug Administration (FDA)-cleared genotyping tests were found. Thus, genotyping is offered as a laboratory-developed test. Clinical laboratories may develop and validate tests in-house (“home-brew”) and market them as a laboratory service; such tests must meet the general regulatory standards of the Clinical Laboratory Improvement Act (CLIA). The laboratory offering the service must be licensed by CLIA for high-complexity testing.
Mutation testing for Rett syndrome may be considered medically necessary to confirm a diagnosis of Rett syndrome in a female child with developmental delay and signs/symptoms of Rett syndrome, but 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, are considered investigational.
Beginning in 2012, there is specific CPT coding for this testing:
81302: MECP2 (methyl CpG binding protein 2)(eg, Rett syndrome) gene analysis; full sequence analysis
81303: known familial variant
81304: duplication/deletion variants
CPT code 81404 includes the following testing for FOXG1:
FOXG1 (forkhead box G1)(eg, Rett syndrome), full gene sequence
CPT code 81406 includes the following testing for CDKL5:
CDKL5 (cyclin-dependent kinase-like 5)(eg., epileptic encephalopathy), full gene sequence
BlueCard/National Account Issues
No applicable information
This policy was created in 2012 and is based on a search of the MEDLINE database through July 2013. 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%. (7)
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. (8) 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. (9) 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 (2006) summarized 6 articles that attempted to disclose a genotype-phenotype correlation, which included the 2 studies outlined above. (2) 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. Two subsequent studies (10, 11) used the InterRett database to examine genotype and RTT severity. Of 357 girls with epilepsy who had MECP2 genotype recorded, those with large deletions were more likely than those with 10 other common mutations to have active epilepsy (odds ratio [OR]: 3.71 (95% confidence interval [CI]: 1.13, 12.17); p=0.03) and had the earliest median age at epilepsy onset (3 years 5 months). Among all girls in the database, those with large deletions were more likely to have never walked (OR: 0.42 (95% CI: 0.22, 0.79), p=0.007). Among 260 girls with classic RTT enrolled in the multicenter RTT Natural History study (NCT00299312), those with the R133C substitution mutation had clinically less severe disease, assessed by the Clinical Severity, Motor Behavior Analysis, and Physician Summary scales. (6)
Conclusions: 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.
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. Because 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%, except in the rare situation where the mother carries the mutation. (12) Therefore, for mothers without the Rett phenotype, it is extremely unlikely that prenatal testing will identify cases of RTT.
Conclusions. 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.
Clinical Input Received through Physician Specialty Societies and Academic Medical Centers
In response to requests, input was received related to the use mutation testing for Rett syndrome in June 2012 from 3 academic medical centers and 2 specialty medical societies (3 reviewers), for a total of 6 reviewers. While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.
There was consensus/near total consensus supporting the use of mutation testing for the diagnosis of Rett syndrome in a girl in whom the clinical differential diagnosis includes Rett syndrome, especially when the clinical diagnosis is uncertain. Support for testing sisters of individuals with Rett syndrome and for prenatal screening was mixed.
Ongoing Clinical Trials
Online site, ClinicalTrials.gov, currently lists several active trials of treatments for RTT: EPI-743, an experimental antioxidant for treatment of mitochondrial disorders (NCT01822249); recombinant insulin-like growth factor-1 (NCT01253317, NCT01777542); and dextromethorphan (NCT01520363).
MECP2 mutations are found in the majority of patients with Rett syndrome (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. (3) 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%,, except in the rare situation where the mother carries the mutation, and the impact on decision making on health outcomes is uncertain.
Therefore, mutation testing for Rett syndrome may be considered medically necessary to confirm a diagnosis of Rett syndrome 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, are considered investigational.
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. (13) 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 is unclear from symptoms alone.
These medical organizations have not yet given recommendations on when to use CDKL5 or FOXG1 testing. However, it has been suggested that patients who are negative for MECP2 mutations and who have a strong clinical diagnosis of RTT should be considered for further screening of the CDKL5 gene if there are early-onset seizures, or the FOXG1 gene if there are congenital features (e.g., severe postnatal microcephaly). (1, 3)
- Williamson SL, Christodoulou J. Rett syndrome: new clinical and molecular insights. Eur J Hum Genet 2006; 14(8):896-903.
- Lotan M, Ben-Zeev B. Rett syndrome. A review with emphasis on clinical characteristics and intervention. ScientificWorldJournal 2006; 6:1517-41.
- Neul JL, Kaufmann WE, Glaze DG et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol 2010; 68(6):944-50.
- Guy J, Gan J, Selfridge J et al. Reversal of neurological defects in a mouse model of Rett syndrome. Science 2007; 315(5815):1143-47.
- Robinson L, Guy J, McKay L et al. Morphological and functional reversal of phenotypes in a mouse model of Rett syndrome. Brain 2012; 135(9):2699-710.
- Lane JB, Lee HS, Smith LW et al. Clinical severity and quality of life in children and adolescents with Rett syndrome. Neurology 2011; 77(20):1812-8.
- http://www.aruplab.com/guides/ug/tests/0051614.jsp. Last accessed August, 2013.
- Huppke P, Laccone F, Kramer N et al. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum Mol Genet 2000; 9(9):1369-75.
- Cheadle JP, Gill H, Fleming N et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum Mol Genet 2000; 9(7):1119-29.
- Bao X, Downs J, Wong K et al. Using a large international sample to investigate epilepsy in Rett syndrome. Dev Med Child Neurol 2013; 55(6):553-58.
- Bebbington A, Downs J, Percy A et al. The phenotype associated with a large deletion on MECP2. Eur J Hum Genet 2012; 20(9):921-7.
- Amir RE, Sutton VR, Van den Veyver IB. Newborn screening and prenatal diagnosis for Rett syndrome: implications for therapy. J Child Neurol 2005; 20(9):779-83.
- Michelson DJ, Shevell MI, Sherr EH et al. 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.
|CPT||81302||MECP2 (methyl CpG binding protein 2)(eg, Rett syndrome) gene analysis; full sequence analysis|
|81303||MECP2 (methyl CpG binding protein 2)(eg, Rett syndrome) gene analysis; known familial variant|
|MECP2 (methyl CpG binding protein 2)(eg, Rett syndrome) gene analysis; duplication/deletion variants|
|ICD-9-CM Diagnosis||Investigational for all diagnoses|
|ICD-10-CM (effective 10/1/14)||Investigational for all diagnoses|
|Z13.4||Encounter for screening for certain developmental disorders in childhood|
|ICD-10-PCS (effectve 10/1/14)||Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests.|
Genetic Testing, Rett Syndrome
MECP2, Genetic Testing
|07/12/12||Add to Medicine -Pathology/Laboratory section||New policy. Policy statements state that mutation testing for Rett syndrome may be considered medically necessary to confirm a diagnosis of Rett syndrome in a female child with developmental delay and signs/symptoms of Rett syndrome, but 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, are considered investigational.|
|8/09/12||Replace policy- correction only||Last paragraph of the Summary section revised for clarification and diagnosis codes added to code table.|
|9/12/13||Replace policy||Policy updated with a literature search through July 2013; references 3-6, 10 and 11 added. Policy statements unchanged.|