CPT 81302, 81303, 81304, 81404, 81406 - Rett syndrome

Coding  Code Description 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

81304 MECP2 (methyl CpG binding protein 2) (eg, Rett syndrome) gene analysis; duplication/deletion variants

81404 Molecular pathology procedure, Level 5 (eg, analysis of 2-5 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis)

81406 Molecular pathology procedure, Level 7 (eg, analysis of 11-25 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 26-50 exons, cytogenomic array analysis for neoplasia)

81599 Unlisted multianalyte assay with algorithmic analysis






Introduction

Rett syndrome is a rare disorder of the nervous system that affects mostly girls. This disorder influences how the brain develops. A girl with Rett syndrome grows normally for about the first six to eighteen months. Then, noticeable changes develop. The child’s loses the muscle ability she had already developed, so activities like crawling, walking, or using the hands begin to diminish. (Some boys also develop Rett syndrome but because of their chromosomal makeup they die before birth or as early in infancy.) A genetic change (mutation) is responsible for Rett syndrome. But this genetic change usually isn’t inherited from a parent. It most often occurs by chance. Rett syndrome can’t be cured. However, treatments can be used to help manage symptoms and provide support. Such care is usually needed throughout life. A genetic test is available to see if a person has Rett syndrome. This policy describes when the genetic test may be considered medically necessary.



Service Medical Necessity

Genetic testing for Rett syndrome

Targeted genetic testing for a known familial Rett syndrome*associated variant

Genetic testing for Rett syndrome *associated genes (eg, MECP2, FOXG1, or CDKL5) may be considered medically necessary when the following criteria are met: * 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
Testing for that variant is medically necessary to determine carrier status of a mother or a sister of an individual with Rett syndrome.
Service Investigational

All other indications for genetic testing for Rett syndrome*associated genes

All other indications for genetic testing for Rett syndrome associated genes (eg, MECP2, FOXG1, or CDKL5) are considered investigational including: * Routine carrier testing (preconception or prenatal) in persons  with negative family history of Rett syndrome AND * Testing of asymptomatic family members to determine future  risk of the disease  



Related Information 

Genetics Nomenclature Update

The Human Genome Variation Society 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, 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  Previous  Updated  Definition

Mutation Disease-associated variant Disease-associated change in the DNA sequence


Previous  Updated  Definition
Variant Change in the DNA sequence 
Familial variant Disease-associated variant identified in a proband for use in subsequent targeted genetic testing in first-degree relatives

Table 2. ACMG-AMP Standards and Guidelines for Variant Classification
Variant Classification Definition
Pathogenic Disease-causing change in the DNA sequence
Likely pathogenic Likely disease-causing change in the DNA sequence 
Variant of uncertain significance Change in DNA sequence with uncertain effects on disease
Likely benign Likely benign change in the DNA sequence
Benign Benign change in the DNA sequence
ACMG: American College of Medical Genetics and Genomics; AMP: Association for Molecular Pathology.

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 the understanding of 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; further, genetic counseling should be performed by an individual with experience and expertise in genetic medicine and genetic testing methods.

Evidence Review 

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 a patient with clinical features of RTT or a patient’s family member. 

Background
Rett Syndrome

Rett syndrome (RTT) is a severe neurodevelopmental disorder primarily affecting girls, with an incidence of 1 in 10,000 female births, 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 stereotypical 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 

Currently, there are no specific treatments that halt or reverse disease progression, 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.

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 *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, and physical therapy and hydrotherapy may prolong mobility. Occupational therapy can help children develop communication strategies and skills needed for performing self-directed activities (eg, dressing, feeding, practicing arts and crafts).

Pharmacologic approaches to managing problems associated with RTT include melatonin for sleep disturbances and several agents to control 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.

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%, while large deletions are responsible for 8% to 10%.

MECP2 variant type is associated with disease severity.

Whole duplications of the MECP2 gene have been associated with 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.


Because the spectrum of clinical phenotypes is broad, to facilitate genotype-phenotype correlation analyses, the International Rett Syndrome Association has established a locusspecific 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 a 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 having 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% (because 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, PPMsyndrome (an X-linked genetic disorder characterized by psychotic disorders [most commonlbipolar disorder], parkinsonism, and intellectual disability), autism, and neonatal encephalopathy.

Recent studies have revealed that different classes of genetic variants inMECP2 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, FOXG1) have been shown to be associated with atypical variants.