Coverage Policy Manual
Policy #: 2004046
Category: Laboratory
Initiated: July 2004
Last Review: June 2018
  Genetic Test: FMR 1 Mutations Including Fragile X Syndrome

Description:
Fragile X syndrome is the most common inherited form of mental disability and known genetic cause of autism. The diagnosis includes use of a genetic test that determines the number of CGG repeats in the fragile X gene.
 
Background
Fragile X syndrome
Fragile X syndrome (FXS) is the most common cause of heritable mental retardation, characterized by moderate mental retardation in males and mild mental retardation in females. FXS affects approximately one in 4,000 males and one in 8,000 females. In addition to the intellectual impairment, patients present with typical facial characteristics 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 disorders, 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.
 
Approximately 1-3% of children ascertained on the basis of autism diagnosis are shown to have fragile X syndrome, with expansion of the CGG trinucleotide repeat in the FMR1 gene to full mutation size of 200 or more repeats. A considerable number of children being evaluated for autism have been found to have FMR1 premutations (55-200 CGG repeats) (Miles, 2011). In one author’s experience, 2% of persons ascertained through a dedicated autism clinic had either an FMR1 full mutation or premutation.
 
Treatment of Fragile X Syndrome
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, special educational services, and behavioral interventions. Medication management may be indicated to modify attention deficits, problems with 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.
 
Genetics of Fragile X syndrome
FXS is associated with the expansion of the CGG trinucleotide repeat in the fragile X mental retardation 1 (FMR1) gene on the X chromosome. Diagnosis of FXS may include using a genetic test that determines the number of CGG repeats in the fragile X gene. The patient is classified as normal, intermediate (or “gray zone”), permutation, or full mutation based on the number of CGG repeats (Monaghan, 2013):
 
• Full mutation: >200-230 CGG repeats (methylated)
 
• Premutation: 55-200 CGG repeats (unmethylated)
 
• Intermediate: 45-54 CGG repeats (unmethylated)
 
• Normal: 5-44 CGG repeats (unmethylated)
 
Full mutations are associated with FXS, which is caused by expansion of the FMR1 gene CGG triplet repeat above 200 units in the 5’ untranslated region of FMR1, leading to hypermethylation of the promoter region followed by transcriptional inactivation of the gene. FXS is caused by a loss of the fragile X mental retardation protein (FMRP).
 
Patients with a premutation are carriers and may develop an FMR1-related disorder, such as fragile X-associated tremor/ ataxia syndrome (FXTAS) or, in women, fragile X-associated premature ovarian insufficiency (FXPOI). FXTAS is a late-onset syndrome, comprising progressive development of intention tremor and ataxia, often accompanied by progressive cognitive and behavioral difficulties, including memory loss, anxiety, reclusive behavior, deficits of executive function, and dementia.
Premutation alleles in females are unstable and may expand to full mutations in offspring. Premutations of fewer than 59 repeats have not been reported to expand to a full mutation in a single generation. Premutation alleles in males may expand or contract by several repeats with transmission; however, expansion to full mutations has not been reported.
 
Premutation allele prevalence in Caucasians is approximately1 in 1000 males and 1 in 350 females.(3-5) Full mutations are typically maternally transmitted. The mother of a child with an FMR1 mutation is almost always a carrier of a premutation or full mutation. Women with a premutation are at risk of premature ovarian insufficiency and at small risk of FXTAS; they carry a 50% risk of transmitting an abnormal gene, which contains either a premutation copy number (55-200) or a full mutation (>200) in each pregnancy.
 
Men who are premutation carriers are referred to as transmitting males. All of their daughters will inherit a premutation, but their sons will not inherit the premutation. Males with a full mutation usually have mental retardation and decreased fertility.
  
Regulatory Status
No 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.
 
Asuragen offers the Xpansion Interpreter™ test which analyzes AGG sequences that interrupt the CGG repeats which have been suggested to stabilize alleles and protect against expansion in subsequent generations.
 
Effective in 2012, there are specific CPT codes for this testing:
81243: FMR1 (Fragile X mental retardation 1) (e.g., fragile X mental retardation) gene analysis; evaluation to detect abnormal (e.g., expanded) alleles
81244: FMR1 (Fragile X mental retardation 1) (e.g., fragile X mental retardation) gene analysis; characterization of alleles (e.g., expanded size and methylation status)
 

Policy/
Coverage:
Effective June 2017
 
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
 
Genetic testing for FMR1 mutations meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following patient populations:
  • Individuals of either sex with mental retardation, developmental delay, or autism spectrum disorder. This would include testing of amniotic fluid or chorionic villus sampling to determine the status of a fetus
  • Prenatal testing of fetuses of known carrier mothers.
  • Testing of an infant born of a parent with known family history of Fragile X syndrome.
  • Women with primary ovarian failure under the age of 40 in whom fragile X-associated ovarian failure is suspected.
  • Individuals with neurologic symptoms consistent with fragile X-associated tremor/ataxia syndrome.
 
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
 
Genetic testing for FMR1 mutations in all other situations does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
 
Testing of the parent(s) or prospective parent(s) to determine if the parent(s) has the recessive gene is a contract exclusion.
 
Fragile X testing for children with isolated attention-deficit/hyperactivity (ADHD, 2011) is a contract exclusion.
 
Effective Prior to June 2017
 
Genetic testing for FMR1 mutations meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes for the following patient populations:
    • Individuals of either sex with mental retardation, developmental delay, or autism spectrum disorder.  This would include testing of amniotic fluid or chorionic villus sampling to determine the status of a fetus
    • Prenatal testing of fetuses of known carrier mothers.  
    • Testing of an infant born of a parent with known family history of Fragile X syndrome.
 
Testing of the parent(s) or prospective parent(s) to determine if the parent(s) has the recessive gene is a contract exclusion.
 
Fragile X testing for children with isolated attention-deficit/hyperactivity (ADHD, 2011) is a contract exclusion.
 
 
Effective prior to June 2012
Genetic testing for Fragile X syndrome meets primary coverage criteria for effectiveness and is covered in the following circumstances:
    • Testing of an affected infant or child to determine if the developmental delay demonstrated by the affected child is Fragile X syndrome.  This would include testing of amniotic fluid or chorionic villus sampling to determine the status of a fetus.
    • Testing of an infant born of a parent with known family history of Fragile X syndrome.
 
Testing of the parent(s) or prospective parent(s) to determine if the parent(s) has the recessive gene is a contract exclusion.
 
 

Rationale:
Analytic validity/Clinical validity
Analytic validity refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent and clinical validity refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease.
 
The analytic and clinical validity are the same for FXS as the diagnosis of FXS is based upon the detection of an alteration in the FMR1 gene.
 
According to a large reference laboratory, the analytical sensitivity and specificity of FMR1 screen with reflex to FMR1 diagnostic, FMR1 diagnostic, and FMR1 fetal diagnostic, is 99% (ARUP Laboratory). According to this same large reference laboratory, the clinical sensitivity and specificity is 99% for premutation and full mutation alleles (ARUP Laboratory).  
 
DNA studies are used to test for fragile X syndrome. Genotypes of individuals with symptoms of FXS and individuals at risk for carrying the mutation can be determined by examining the size of the trinucleotide repeat segment and the methylation status of the FMR1 gene. Two main approaches are used: polymerase chain reaction (PCR) and Southern blot analysis.
 
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 about 100-150 CGG. As a result, Southern blot analysis is commonly used to determine the number of triplet repeats in FXS.
 
PCR analysis utilizes flanking primers to amplify a fragment of DNA spanning the repeat region. Thus, the sizes of the PCR products are indicative of the approximate number of repeats present in each allele of the individual being tested. The efficiency of the PCR reaction 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 the FMR1 methylation status, are limitations of the PCR approach. On the other hand, PCR analysis permits accurate sizing of alleles in the normal, the “gray zone,” and the premutation size ranges on small amounts of DNA in a relatively short turnaround time. Also, the assay is not affected by skewed X-chromosome inactivation.
 
Quality assessment schemes have shown a wide disparity in allele sizing between laboratories (Hawkins, 2011).  Therefore, a panel of genotyping reference materials for FXS syndrome was developed, which is expected to be stable over many years and available to all diagnostic laboratories. A panel of five genomic DNA samples 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. Patient blood samples were collected from six consenting donors; one donor was a normal female individual and the remainder had been identified after previous molecular genetic investigation. Classifications of these patients were: female pre-mutation, male pre-mutation, male full mutation and female full mutation (×2). In all, 38 laboratories were invited to take part in the study, 23 laboratories agreed to participate and results were returned by 21 laboratories. The participating twenty-one laboratories from seventeen countries evaluated the samples (blinded, in triplicate) in their routine methods alongside in-house and commercial controls. Seventeen different countries were represented among participants who returned the results: 13 from Europe, 4 from North America, 3 from Australasia and 1 from Asia. Collaborative validation study participants were requested to test the 18 coded samples on three separate days using different lots of reagents or different operators if possible. A total of 18 non-consensus results were reported, giving an overall rate of non-concordance of 4.9% (21 laboratories × 18 samples – 7 samples not tested), although these were clustered in three laboratories. There was no correlation between the non-concordant results and any particular sample or a specific method. One laboratory reported 12 of the 18 non-concordant results. This laboratory was contacted, and their testing protocol was changed.
 
CGG-repeat expansion full mutations account for >99% of cases of FXS. Therefore, tests that effectively detect and measure the CGG repeat region of the FMR1 gene are >99% sensitive. Positive results are 100% specific. There are no known forms of FMRP deficiency that do not map to the FMR1 gene.
 
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)
 
Evidence on the clinical benefit of testing for FXS is largely anecdotal. The clinical utility of genetic testing can be considered in the following clinical situations: 1) individuals with a clinical diagnosis of mental retardation, developmental delay, or autism, especially if they have any physical or behavioral characteristics of fragile X syndrome, a family history of fragile X syndrome, or male or female relatives with undiagnosed mental retardation, and 2) individuals seeking reproductive counseling.
 
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 FXS 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 FXS, 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. The American Academy of Pediatrics (AAP) and the American Academy of Neurology (AAN) recommend cytogenetic evaluation to look for certain kinds of chromosomal abnormalities that may be causally related to their condition. The AAN guidelines note that only in occasional cases will an etiologic diagnosis lead to specific therapy that improves outcomes but suggest the more immediate and general clinical benefits of achieving a specific genetic diagnosis from the clinical viewpoint, as follows:
 
• limit additional diagnostic testing;
• anticipate and manage associated medical and behavioral comorbidities;
• improve understanding of treatment and prognosis; and
• allow counseling regarding risk of recurrence in future offspring and help with reproductive planning.
 
AAP and AAN guidelines also emphasize the importance of early diagnosis and intervention in an attempt to ameliorate or improve behavioral and cognitive outcomes over time.
 
Hersh and colleagues reported on families with an affected male and whether an early diagnosis would have influenced their reproductive decision-making (Hersh, 2011). After a diagnosis in the affected male was made, 73% of families reported that the diagnosis of FXS affected their decision to have another child, and 43% of the families surveyed had had a second child with a full mutation.
 
Testing the repeat region of the FMR1 gene in the context of reproductive decision making may include testing individuals with either a family history of FXS or a family history of undiagnosed mental retardation, fetuses of known carrier mothers, or in 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 (because the cytogenetic test was used prior to the identification of the FMR1 gene and is significantly less accurate than the current DNA test. DNA testing would accurately identify premutation carriers and distinguish premutation from full mutation carrier women.)
 
Practice Guidelines and Position Statements
The American College of Medical Genetics (ACMG) Professional Practice and Guidelines Committee make the following recommendations regarding diagnostic and carrier testing for fragile X syndrome:
 
The purpose of these recommendations is to provide general guidelines to aid clinicians in making referrals for testing the repeat region of the FMR1 gene.
● Individuals of either sex with mental retardation, developmental delay, or autism, especially if they have (a) any physical or behavioral characteristics of fragile X syndrome, (b) a family history of fragile X syndrome, or (c) male or female relatives with undiagnosed mental retardation.
● Individuals seeking reproductive counseling who have (a) a family history of fragile X syndrome or (b) a family history of undiagnosed mental retardation.
● Fetuses of known carrier mothers.
● Affected individuals or their relatives in the context of a positive cytogenetic fragile X test result who are seeking further counseling related to the risk of carrier status among themselves or their relatives. The cytogenetic test was used prior to the identification of the FMR1 gene and is significantly less accurate than the current DNA test. DNA testing on such individuals is warranted to accurately identify premutation carriers and to distinguish premutation from full mutation carrier women (Sherman, 2005).
 
In the clinical genetics evaluation in identifying the etiology of autism spectrum disorders, the ACMG recommends testing for FXS as part of first tier testing (Schaefer, 2008).
 
The American Academy of Pediatrics recommends that, because children with FXS may not have apparent physical features, any child who presents with developmental delay, borderline intellectual abilities, or mental retardation or has a diagnosis of autism without a specific etiology should undergo molecular testing for FXS to determine the number of CGG repeats (Hersh, 2011).  
 
The American College of Obstetricians and Gynecologists (ACOG) recommends that prenatal testing for fragile X syndrome should be offered to known carriers of the fragile X premutation or full mutation, and to women with a family history of fragile X-related disorders, unexplained mental retardation or developmental delay, autism, or premature ovarian insufficiency.
 
Summary
Fragile X syndrome is the most common inherited cause of intellectual disabilities and the most common genetic cause of autism. The genetics of fragile X syndrome are complex, and there is a broad spectrum of clinical involvement throughout the generations of families affected by the fragile X mutations. A thorough family history, patient assessment and genetic counseling should guide testing for individuals affected by the many manifestations of these mutations. Analytic sensitivity and specificity for diagnosing these disorders has been demonstrated to be sufficiently high.
 
There are a variety of ways management may change as a result of genetic testing. Evidence on the impact on health outcomes of documenting FMR1 gene mutations is largely anecdotal, but may end the need for additional testing in the etiologic workup of an intellectual disability, aid in management of psychopharmacologic interventions, and assist in reproductive decision making.
 
  
2014 Update
A literature search conducted through May 2014 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
According to a large reference laboratory, analytic sensitivity and specificity of FMR1 screen with reflex to FMR1 diagnostic, FMR1 diagnostic, and FMR1 fetal diagnostic, is 99% (ARUP, 2014a; ARUP, 2014b) Clinical sensitivity and specificity is 99% for premutation and full mutation alleles. Diagnostic errors can occur due to rare sequence variations.
 
DNA studies are used to test for fragile X syndrome. Genotypes of individuals with symptoms of FXS and individuals at risk for carrying the mutation 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 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 100-150 CGG repeats. Consequently, Southern blot analysis is commonly used to determine the number of triplet repeats in FXS and methylation status.
 
PCR analysis utilizes 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 the PCR reaction 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 thenormal 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 (Monaghan, 2013).
 
Unlike PCR, Southern blotting is time-consuming and requires large amounts of DNA. Alternatives to Southern blotting for determining FMR1 methylation status are in development. These include methylation-sensitive PCR and methylation-specific melting curve analysis (Grasso, 2014; Gatto, 2013; Chaudhary, 2014; Inaba, 2014).
 
2015 Update
A literature search conducted through May 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
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 (Lim, 2015). For detecting expansions of more than 55 CGG repeats in FMR1, sensitivity and specificity were 100% (95% confidence interval [CI], 91 to 100) and 100% (95% CI, 99 to 100), respectively.
 
Ongoing and Unpublished Clinical Trials
A search of ClinicalTrials.gov in May 2015 did not identify any ongoing or unpublished trials that would likely influence this policy.
 
2016 Update
A literature search conducted through May 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through May 2017 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
 
ANALYTIC VALIDITY AND CLINICAL VALIDITY
Analytic validity refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent. Clinical validity refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease. However, the diagnosis of FXS is based on detection of an alteration in the FMR1 gene.
 
CLINICAL UTILITY
FXS, FXTAS, and FXPOI
Clinical utility refers to how results of the diagnostic test will be used to change patient management and whether these changes in management lead to clinically important improvements in health outcomes.
 
However, the conditions caused by abnormal CGG repeats in the FMR1 gene, FXS, FXTAS, and FXPOI, do not have specific treatments that alter the natural history of the disorders. However, because they represent relatively common causes of conditions that are often difficult to diagnose and involve numerous diagnostic tests, the capability of FMR1 testing to obtain an accurate definitive diagnosis and avoid additional diagnostic testing supports its clinical utility. Knowledge that the condition is caused by fragile X provides important knowledge to offspring and the risk of disease in subsequent generations.
 
2018 Update
A literature search conducted using the MEDLINE database through May 2018 did not reveal any new information that would prompt a change in the coverage statement.
 
There were no new clinical trials identified. Two practice guidelines were reviewed and summarized.
 
Academy of Pediatrics
The Academy of Pediatrics (2014) recommended that fragile X testing be performed in any child who presents with global developmental delay or intellectual disability without a specific etiology (Moeschler, 2014). FMR1 testing for CGG repeat length is considered a first-line test by the Academy and will identify 2% to 3% of boys with global developmental delay/intellectual disability and 1% to 2% of girls (full mutation).
 
American College of Obstetricians and Gynecologists
In 2017, the American College of Obstetricians and Gynecologists recommended that screening for FXS be offered to women with a family history suggestive of FXS and to women with a medical history suggestive of being a fragile X carrier (ie, ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40) (ACOG, 2017). The College recommended prenatal diagnostic testing for FXS to known carriers of the fragile X premutation or full mutation.

CPT/HCPCS:
81171AFF2 (AF4/FMR2 family, member 2 [FMR2]) (eg, fragile X mental retardation 2 [FRAXE]) gene analysis; evaluation to detect abnormal (eg, expanded) alleles
81172AFF2 (AF4/FMR2 family, member 2 [FMR2]) (eg, fragile X mental retardation 2 [FRAXE]) gene analysis; characterization of alleles (eg, expanded size and methylation status)
81243FMR1 (fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; evaluation to detect abnormal (eg, expanded) alleles
81244FMR1 (fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; characterization of alleles (eg, expanded size and methylation status)

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