Genetic Testing for Rett Syndrome

POLICY NUMBER

L.2.04.461

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 variant exists in RTT-associated genes (eg, MECP2, FOXG1, or CDLK5) in an individual with clinical features of Rett syndrome or in an individual's family member.

Rett syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting girls, with an incidence of 1 in 10,000 female births and a prevalence of 7.1 per 100,000 females, making it among the most common genetic causes of intellectual disability in girls. In its typical form, RTT is characterized by apparently normal development for the first 6 to 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, such as hand-wringing. Other clinical manifestations include seizures, disturbed breathing patterns with hyperventilation and periodic apnea, scoliosis, growth retardation, and gait apraxia.

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 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. 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

Management of RTT is mainly symptomatic and individualized, focusing on optimizing each individual's abilities. 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, practicing arts and crafts).

Trofinetide (Daybue) is the first and only approved drug for Rett syndrome in adults and pediatric patients ≥2 years of age. In the pivotal 12-week LAVENDAR trial comparing trofinetide (n=93) to placebo (n=94) in female patients with Rett syndrome, statistically significant improvements were observed in the Rett Syndrome Behavior Questionnaire (RSBQ) score and Clinical Global Impression-Improvement (CGI-I) score. However, the clinical significance of these findings is uncertain.

Additional pharmacologic approaches to managing problems associated with RTT include melatonin for sleep disturbances and several agents to control breathing disturbances, seizures, gastrointestinal issues, urinary retention, 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.

Genetics

RTT is an X-linked dominant genetic disorder. Pathogenic variants in the 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 patients with classic RTT have pathogenic variants in the MECP2 gene. More than 200 pathogenic variants in MECP2 have been associated with RTT. However, 8 of the most commonly occurring missense and nonsense variants account for almost 70% of all cases; small C-terminal deletions account for approximately 10%; and large deletions, 8% to 10%. MECP2 variant type is associated with disease severity. Whole duplications of the MECP2 gene have been associated with a severe X-linked intellectual disability with progressive spasticity, no or poor speech acquisition, and acquired microcephaly. Additionally, 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 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).

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. Recent studies have revealed that different classes of genetic variants in MECP2 result in variable clinical phenotypes and overlap with other neurodevelopmental disorders.

A proportion of patients with a clinical diagnosis of RTT do not appear to have pathogenic variants in the MECP2 gene. Two other genes (CDKL5 and FOXG1) have been shown to be associated with atypical variants.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service;laboratory-developed tests (LDTs) 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 LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of this test.

POLICY

Genetic testing for Rett syndrome-associated genes (eg, MECP2, FOXG1, or CDKL5) may be considered medically necessary to establish a genetic diagnosis of Rett syndrome in a child with developmental delay and signs/symptoms of Rett syndrome, when a definitive diagnosis cannot be made without genetic testing.

Targeted genetic testing for a known familial Rett syndrome-associated variant may be considered medically necessary to determine carrier status of first-degree female relatives (a mother or a sister) of an individual with Rett syndrome.

All other indications for genetic testing for Rett syndrome-associated genes (eg, MECP2, FOXG1, or CDKL5), including routine carrier testing (preconception or prenatal) in persons with negative family history, and testing of asymptomatic family members to determine future risk of disease, are considered investigational.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Genetics Nomenclature Update

The Human Genome Variation Society (HGVS) nomenclature is used to report information on variants found in DNA and serves as an international standard in DNA diagnostics. It is being implemented for genetic testing medical evidence review updates starting in 2017 (see Table 1). The Society's nomenclature is recommended by the Human Variome Project, the HUman Genome Organization (HUGO) and by the Human Genome Variation Society itself.

The American College of Medical Genetics and Genomics and the Association for Molecular Pathology standards and guidelines for interpretation of sequence variants represent expert opinion from both organizations, in addition to the College of American Pathologists. These recommendations primarily apply to genetic tests used in clinical laboratories, including genotyping, single genes, panels, exomes, and genomes. Table 2 shows the recommended standard terminology—“pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign”—to describe variants identified that cause Mendelian disorders.

Table 1. Nomenclature to Report on Variants Found in DNA

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification

Genetic Counseling

Experts recommend formal genetic counseling for patients who are at risk for inherited disorders and who wish to undergo genetic testing. Interpreting the results of genetic tests and understanding risk factors can be difficult for some patients; genetic counseling helps individuals understand the impact of genetic testing, including the possible effects the test results could have on the individual or their family members. It should be noted that genetic counseling may alter the utilization of genetic testing substantially and may reduce inappropriate testing. Genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

11/15/2012: Approved by Medical Policy Advisory Committee.

11/15/2013: Policy reviewed; no changes.

10/20/2014: Policy reviewed; description updated regarding genetics of Rett Syndrome. Policy statement unchanged.

08/18/2015: Medical policy revised to add ICD-10 codes.

02/15/2016: Policy description updated regarding treatment of Rett Syndrome and testing. Policy statements updated for clarification. Medically necessary statement updated to change "but when there is uncertainty in the clinical diagnosis" to "when a definitive diagnosis cannot be made without genetic testing." Investigational statement updated to change "prenatal screening" to "carrier testing (preconception or prenatal)." It previously stated: All other indications for mutation testing for Rett syndrome, including prenatal screening and testing of family members, are considered investigational. Policy guidelines updated regarding genetic counseling and to add medically necessary and investigational definitions.

06/07/2016: Policy number A.2.04.81 added.

09/14/2017: Policy revised to change "mutations" to "variants" throughout the policy. Policy description updated regarding diagnostic criteria for typical and atypical Rett Syndrome. Policy statements updated to change "mutation testing" to "genetic testing." Medically necessary policy statement updated to add "Rett syndrome-associated genes (eg, MECP2, FOXG1, or CDKL5)" and to remove "female." Added medically necessary statement that targeted genetic testing for a known familial Rett syndrome-associated variant may be considered medically necessary to determine carrier status of a mother or a sister of an individual with Rett syndrome. Policy statement updated to add that all other indications for genetic testing for Rett syndrome-associated genes (eg, MECP2, FOXG1, or CDKL5) are considered investigational. Policy Guidelines updated to add standard terminology for variant classification. Code Reference section updated to add CPT codes 81404 and 81406.

12/22/2017: Code Reference section updated to revise descriptions for CPT codes 81404 and 81406 effective 01/01/2018.

06/13/2018: Policy description updated regarding atypical variants. Policy statement revised to clarify that all other indications, including carrier testing "in persons with negative family history" is considered investigational. Policy Guidelines updated regarding genetics nomenclature and genetic counseling.

06/06/2019: Policy reviewed; no changes.

06/18/2020: Policy reviewed; no changes.

12/17/2020: Code Reference section updated to add new CPT code 0234U, effective 01/01/2021.

08/02/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

06/17/2022: Policy description updated to change "patient" to "individual." Policy statement regarding targeted genetic testing updated to add "first-degree female relatives." Investigational statement updated to change "carrier testing" to "routine carrier testing." Policy intent unchanged.

07/12/2023: Policy description updated regarding Rett syndrome. Policy statements unchanged.

06/17/2024: Policy description updated regarding treatment of Rett syndrome. Policy statements unchanged.

08/28/2024: Policy updated to change the medical policy number from “A.2.04.81” to “L.2.04.461.”

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.81

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Covered Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.