Genetic Testing for FMR1 Variants (including Fragile X Syndrome)

POLICY NUMBER

A.2.04.83

DESCRIPTION

Fragile X syndrome (FXS) is the most common inherited form of mental disability and a known genetic cause of autism. The diagnosis is made with a genetic test that determines the number of CGG repeats in the fragile X mental retardation 1 gene, (FMR1). FMR1 variant testing has been investigated in a variety of clinical settings, including the evaluation of individuals with a personal or family history of intellectual disability, developmental delay, or autism spectrum disorder and in reproductive decision making in individuals with known FMR1 variants or positive cytogenetic fragile X testing. FMR1 variants also cause premature ovarian failure and a neurologic disease called fragile X-associated ataxia or tremor syndrome.

Diagnosis of Fragile X Syndrome

DNA studies are used to test for fragile X syndrome (FXS). Cytogenetic testing was used before the identification of the fragile X mental retardation 1 (FMR1) gene and is significantly less accurate than the current DNA test. Genotypes of individuals with symptoms of FXS and individuals at risk for carrying the variant can be determined by examining the size of the trinucleotide repeat segment and methylation status of the FMR1 gene. Two main approaches are used: polymerase chain reaction (PCR) and Southern blot analysis.

The polymerase chain reaction analysis uses flanking primers to amplify a fragment of DNA spanning the repeat region. Thus, the sizes of PCR products are indicative of the approximate number of repeats present in each allele of the individual being tested. The efficiency of PCR is inversely related to the number of CGG repeats, so large mutations are more difficult to amplify and may fail to yield a detectable product in the PCR assay. This, and the fact that no information is obtained about FMR1 methylation status, are limitations of the PCR approach. On the other hand, PCR analysis permits accurate sizing of alleles in the normal zone, the “gray zone,” and premutation range on small amounts of DNA in a relatively short turnaround time. Also, the assay is not affected by skewed X-chromosome inactivation.

The difficulty in fragile X testing is that the high fraction of GC bases in the repeat region makes it extremely difficult for standard PCR techniques to amplify beyond 100 to 150 CGG repeats. Consequently, Southern blot analysis is commonly used to determine the number of triplet repeats in FXS and methylation status. Alternatives to Southern blotting for determining FMR1 methylation status have been developed. These include methylation-sensitive PCR and methylation-specific melting curve analysis. One test currently available in Europe (FastFraX; TNR Diagnostics, Singapore) combines a direct triplet repeat-primed PCR with melting curve analysis for detecting CGG expansions.Asuragen offers the Xpansion Interpreter® test, which analyzes AGG sequences that interrupt CGG repeats and may stabilize alleles, protecting against expansion in subsequent generations. Asuragen also markets AmplideX® Fragile X Dx and Carrier Screen Kit, which is the first test approved by the U.S. Food and Drug Administration (FDA).

In 2011, a panel of genotyping reference materials for FXS was developed and is expected to be stable over many years and available to all diagnostic laboratories. A panel of 5 genomic DNA samples (normal female, female premutation, male premutation, male full mutation, and female full mutation) was endorsed by the European Society of Human Genetics and approved as an International Standard by the Expert Committee on Biological Standardization at the World Health Organization.

Treatment

Current approaches to therapy are supportive and symptom-based. Psychopharmacologic intervention to modify behavioral problems in a child with fragile X syndrome may represent an important adjunctive therapy when combined with other supportive strategies including speech therapy, occupational therapy, and special education services. Medication management may be indicated to modify attention deficits, impaired impulse control, and hyperactivity. Anxiety-related symptoms, including obsessive-compulsive tendencies with perseverative behaviors, also may be present and require medical intervention. Emotional lability and episodes of aggression and self-injury may be a danger to the child and others around him or her; therefore, the use of medication(s) to modify these symptoms also may significantly improve an affected child’s ability to participate more successfully in activities in home and school settings.

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). The Xpansion Interpreter test is available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. Until 2020, the U.S. Food and Drug Administration had chosen not to require any regulatory review of this test.

In February 2020, AmplideX Fragile X Dx and Carrier Screen Kit (Asuragen) was granted a de novo 510(k) classification by the FDA. The new classification applies to this device and substantially equivalent devices of this generic type. AmplideX Fragile X Dx and Carrier Screen Kit is cleared for diagnosis of FXS in conjunction with family history and clinical signs and symptoms. The test may also be used for carrier testing, but it is not indicated for fetal diagnostic testing, the screening of eggs obtained for in vitro fertilization prior to implantation, or stand alone diagnoses of FXS. AmplideX quantifies the number of CGG repeats in the FMR1 alleles using PCR with gene-specific and triplet repeat primers followed by size resolution with capillary electrophoresis.

Related policies are -

• Genetic Testing for Developmental Delay/Intellectual Disability, Autism Spectrum Disorder, and Congenital Anomalies

POLICY

Genetic testing for FMR1 variants may be considered medically necessary for the following populations:

• Individuals with characteristics of fragile X syndrome or a fragile X-associated disorder, including:

  • Individuals with intellectual disability, developmental delay, or autism spectrum disorder;

  • Women with primary ovarian insufficiency under the age of 40 in whom fragile X-associated primary ovarian insufficiency is suspected;

  • Individuals with neurologic symptoms consistent with fragile X-associated tremor or ataxia syndrome.

• Individuals who have a personal or family history of fragile X syndrome who are seeking reproductive counseling, including:

  • Individuals who have a family history of fragile X syndrome or a family history of undiagnosed intellectual disability;

  • Affected individuals or relatives of affected individuals who have had a positive cytogenetic fragile X test result who are seeking information on carrier status;

  • Prenatal testing of fetuses of known carrier mothers.

Genetic testing for FMR1 variants is investigational for all other uses.

POLICY EXCEPTIONS

None

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.

Physical and behavioral characteristics of fragile X syndrome include typical facial features, such as an elongated face with a prominent forehead, protruding jaw, and large ears. Connective tissue anomalies include hyperextensible finger and thumb joints, hand calluses, velvet-like skin, flat feet, and mitral valve prolapse. The characteristic appearance of adult males includes macroorchidism. Patients may show behavioral problems including autism spectrum disorder, sleeping problems, social anxiety, poor eye contact, mood disorders, and hand-flapping or biting. Another prominent feature of the disorder is neuronal hyperexcitability, manifested by hyperactivity, increased sensitivity to sensory stimuli, and a high incidence of epileptic seizures.

Testing Strategy

Detection of CGG triplet repeats in the FMR1 gene can occur sequentially or in parallel with determination of methylation status:

• In sequential testing, detection of CGG triplet repeats in FMR1 is performed first. If a large number of repeats (eg, >55) is detected, reflex methylation testing can be performed to determine methylation status

• In parallel testing, detection methods such as methylation-specific polymerase chain reaction allow for detection of both the size of CGG triplet repeats in FMR1 and methylation status.

Cytogenetic Testing

Cytogenetic testing was used before the identification of the FMR1 gene and is significantly less accurate than the current DNA test. The method is no longer considered an acceptable diagnostic method according to the American College of Medical Genetics and Genomics standards.

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 (ACMG) and Genomics and the Association for Molecular Pathology (AMP) 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

Genetic counseling is primarily aimed at patients who are at risk for inherited disorders, and experts recommend formal genetic counseling in most cases when genetic testing for an inherited condition is considered. The interpretation of the results of genetic tests and the understanding of risk factors can be very difficult and complex. Therefore, genetic counseling will assist individuals in understanding the possible benefits and harms of genetic testing, including the possible impact of the information on the individual’s family. 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.

10/15/2013: Policy reviewed; no changes.

08/05/2014: Policy description and statement updated to change "mental retardation" to "intellectual disability." Medically necessary policy statement criteria on affected individuals revised to remove "among themselves or their relatives" for clarity. It previously stated:Affected individuals or their relatives who have had a positive cytogenetic fragile X test result who are seeking further counseling related to the risk of carrier status among themselves or their relatives. Policy guidelines section updated to change "with mental retardation" to "who have intellectual disability."

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

11/02/2015: Policy description updated regarding laboratory-developed tests. Policy statements unchanged. Policy guidelines section updated to add medically necessary and investigative definitions.

06/07/2016: Policy number A.2.04.83 added.

02/15/2017: Policy description updated regarding FMR1 variant testing. Policy statement updated to add that genetic testing for FMR1 mutations may be considered medically necessary for women with primary ovarian failure under the age of 40 in whom fragile X-associated ovarian failure is suspected and in individuals with neurologic symptoms consistent with fragile X-associated tremor/ataxia syndrome. Policy guidelines updated regarding cytogenetic testing and genetic counseling.

02/06/2018: Policy title changed from "Genetic Testing for FMR1 Mutations (including Fragile X Syndrome)" to "Genetic Testing for Pathogenic FMR1 Variants (Including Fragile X Syndrome)." Policy description updated regarding diagnosis of fragile X syndrome. Medically necessary criteria updated regarding individuals with characteristics of fragile X syndrome or a fragile X-associated disorder and individuals who have a personal or family history of fragile X syndrome who are seeking reproductive counseling. In policy statements, "mutations" changed to "variants" and "ovarian failure" changed to "ovarian insufficiency." Policy Guidelines updated to add testing strategy.

12/19/2018: Code Reference section updated to add new CPT codes 81171 and 81172. Revised code description for CPT code 81244, effective 01/01/2019.

02/25/2019: Policy reviewed; no changes.

02/11/2020: Policy description updated to remove information regarding Fragile X Syndrome and Fragile X-Associated Disorders. Policy statements unchanged.

03/03/2021: Policy description updated regarding devices. Policy section updated with minor edit; intent unchanged. Policy Guidelines updated to add genetics nomenclature update.

02/14/2022: Policy title updated to change "Mutations" to "Variants." Policy reviewed. Policy statements unchanged.

02/15/2023: Policy reviewed. Medically necessary policy statement criteria updated to add "primary" to fragile X-associated ovarian insufficiency.

12/21/2023: Code Reference section updated to revise the code descriptions for CPT codes 81171, 81172, 81243, and 81244, effective 01/01/2024.

02/19/2024: Policy reviewed; no changes.

03/12/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.04.83 

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

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