CAM 20483

Genetic Testing for FMR1 mutations (including Fragile X Syndrome)

Category:Laboratory   Last Reviewed:January 2020
Department(s):Medical Affairs   Next Review:January 2021
Original Date:July 2012    

Description:
Fragile X syndrome (FXS) is the most common inherited form of mental disability and known genetic cause of autism. The diagnosis is made with a genetic test that determines the number of CGG repeats in the fragile X gene, FMR1. FMR1 variant testing has been investigated in a variety of clinical settings, including in 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.

For individuals who have characteristics of FXS or an FXS-associated disorder, the evidence includes studies evaluating the clinical validity of FMR1 variant testing. Relevant outcomes are test accuracy, test validity, and resource utilization. The evidence demonstrates that FMR1 variant testing can establish a definitive diagnosis of FXS and fragile X-related syndromes when the test is positive for a pathogenic variant. Following a definitive diagnosis, treatment of comorbid conditions may be improved. At a minimum, providing a diagnosis eliminates the need for further diagnostic workup. A chain of evidence supports improved outcomes following FMR1 variant testing. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.  

For individuals who have a personal or family history of FXS who are seeking reproductive counseling, the evidence includes studies evaluating the clinical validity of FMR1 variant testing and the effect on reproductive decisions. Relevant outcomes are test accuracy, test validity, and changes in reproductive decision making. Testing the repeat region of the FMR1 gene in the context of reproductive decision making may include individuals with either a family history of FXS or a family history of undiagnosed intellectual disability, fetuses of known carrier mothers, or 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. DNA testing would accurately identify premutation carriers and distinguish premutation from full mutation carrier women. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.  

Background
FRAGILE X 
Fragile X Syndrome 
Fragile X syndrome (FXS) is the most common cause of heritable intellectual disability, characterized by moderate intellectual disability in males and mild intellectual disability in females. FXS affects approximately 1 in 4,000 males and 1 in 8,000 females. In addition to intellectual impairment, patients present with typical facial features, such as an elongated face with 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. 

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. FXS is associated with the 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, which is believed to play a key role in early brain development and brain function.  

Fragile X—Associated Disorders
Patients with a premutation (55-200 CGG repeats) may develop an FMR1-related disorder, such as fragile X‒associated tremor or ataxia syndrome or, in women, fragile X‒associated premature ovarian insufficiency (FXPOI). Fragile X–associated tremor or ataxia syndrome 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. FXPOI is characterized by ovarian failure before the 40 years of age.   

Diagnosis
DNA studies are used to test for FXS. Cytogenetic testing was used before identification of the 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.  

PCR 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.1,2   

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. They include methylation-sensitive PCR and methylation-specific melting curve analysis.3-6 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.7  

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 FXS 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 the home and school settings. 

Regulatory Status
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 Act (CLIA). Genotyping tests for FMR1 mutations are available under the auspices of CLIA. Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration has chosen not to require any regulatory review of these tests.

Asuragen offers the Xpansion Interpreter® test, which analyzes AGG sequences that interrupt CGG repeats and may stabilize alleles, protecting against expansion in subsequent generations.6,7

Related Policies
20459 Genetic Testing, Including Chromosomal Microarray Analysis and Next-Generation Sequencing Panels, for Prenatal Evaluation and the Evaluation of Children With Developmental Delay/Intellectual Disability or Autism Spectrum Disorder

Policy:

  1. Pre- and post-test genetic counseling is recommended for individuals undergoing FMR1 gene testing.
  2. Diagnostic genetic testing for FMR1 gene CGG repeats and methylation status is considered MEDICALLY NECESSARY for:
    • Males and females with unexplained mental retardation, developmental delay, or autism spectrum disorder, OR
    • Symptomatic individuals with features of Fragile X syndrome or a family history of Fragile X syndrome, OR
    • Females with unexplained ovarian insufficiency, unexplained ovarian failure, or unexplained elevated FSH prior to age 40, OR
    • Individuals with unexplained late-onset tremor-ataxia, OR
    • Fetuses of known FMR1 premutation or full mutation carriers
  3. Carrier screening for FMR1 gene CGG repeat length is considered MEDICALLY NECESSARY for individuals seeking pre-conception or prenatal care when:
    • There is a family history of Fragile X syndrome, OR
    • There is a family history of unexplained mental retardation, developmental delay, or autism spectrum disorder, OR
    • There is a family history of unexplained late-onset tremor ataxia, OR
    • There is a family history of unexplained premature ovarian insufficiency or failure.

Determination of FMR1 gene point mutations is considered NOT MEDICALLY NECESSARY.

Determination of FMR1 gene deletion is considered NOT MEDICALLY NECESSARY.

Population screening for Fragile X syndrome is considered NOT MEDICALLY NECESSARY.

Cytogenetic testing for Fragile X syndrome is considered NOT MEDICALLY NECESSARY.

Testing for the FMRP protein is considered NOT MEDICALLY NECESSARY

Policy Guidelines
Physical and behavioral characteristics of fragile X syndrome include typical facial features, such as an elongated face with 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:

  1. In sequential testing, detection of CGG triplet repeats in FMR1 is performed first. If a large number of repeats (e.g., >55) is detected, reflex methylation testing can be performed to determine methylation status
  2. 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 American College of Medical Genetics and Genomics standards (see Monaghan et al., 2013).  

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.

CODING
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).

Note: CPT code 81243 is used for polymerase chain reaction testing of CGG triplet repeats in FMR1. If a large number of repeats (e.g., >55) is detected, reflex methylation testing (CPT code 81244) can further characterize abnormal alleles (e.g., to differentiate premutation from full mutation alleles).  

Rationale
Evidence reviews assess whether a medical test is clinically useful.A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

INDIVIDUALS WITH CHARACTERISTICS OF A FRAGILE X SYNDROME OR A FRAGILE X–ASSOCIATED DISORDER
Clinical Context and Test Purpose
Fragile X Syndrome
Diagnosis of fragile X syndrome (FXS) may include a genetic test that determines the number of CGG repeats in the fragile X gene. The patient is classified as normal, intermediate ("gray zone"), premutation, or full mutation based on the number of CGG repeats (see Table 1).1 Approximately 1% to 3% of children initially diagnosed with autism are shown to have FXS, with expansion of the CGG trinucleotide repeat in the FMR1 gene to full mutation length.10 A considerable number of children evaluated for autism have been found to have a FMR1 premutation (55-200 CGG repeats).11 Fragile X-associated disorders (fragile X associated premature ovarian insufficiency [FXPOI] and fragile X-associated tremor or ataxia) are associated with a FMR1 premutation (55-200 CGG repeats).

Table 1. Classifications of CGG Repeat Length

Mutation Classification

CGG Repeat Length

Methylation Status

Variant Classification

Full mutation

>200 to 230

Methylated

Pathogenic variant

Premutation

55 to 200

Unmethylated

Pathogenic variant

Intermediate

45 to 54

Unmethylated

Uncertain variant

Normal

5 to 44

Unmethylated

Benign variant

The purpose of FMR1 variant testing in patients who have characteristics of FXS or a fragile X–associated disorder is to provide an accurate diagnosis and improve treatment of the associated behavioral and medical conditions.

The question addressed in this evidence review is: Does FMR1 variant testing in patients with conditions or family history consistent with the presence of a pathogenic FMR1 variant (e.g., premutation or mutation) improve health outcomes?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant populations of interest are:

  • Individuals with characteristics of FXS or a fragile X-associated disorder, including:
    • Individuals of either sex with intellectual disability, developmental delay, or autism spectrum disorder.
    • Women with primary ovarian failure under the age of 40 in whom FXPOI is suspected.
    • Individuals with neurologic symptoms consistent with fragile X-associated tremor or ataxia syndrome.

Interventions
The relevant interventions of interest are testing for FMR1 variant and methylation status

Comparators
Standard clinical evaluation without genetic testing is used to diagnose FXS or a fragile X–associated disorder.

Outcomes
The general outcomes of interest are an accurate diagnosis of patients with FXS or fragile X-associated disorders and improved management of the disorder.

Timing
This test would be performed when characteristics of FXS or fragile X-associated disorders are identified.

Setting
A number of laboratories can assess for the FMR1 variant and methylation status.  

Simplifying Test Terms
There are 3 core characteristics for assessing a medical test. Whether imaging, laboratory, or other, all medical tests must be:

  • Technically reliable
  • Clinically valid
  • Clinically useful.

Because different specialties may use different terms for the same concept, we are highlighting the core characteristics. The core characteristics also apply to different uses of tests, such as diagnosis, prognosis, and monitoring treatment.

Diagnostic tests detect presence or absence of a condition. Surveillance and treatment monitoring are essentially diagnostic tests over a time frame. Surveillance to see whether a condition develops or progresses is a type of detection. Treatment monitoring is also a type of detection because the purpose is to see if treatment is associated with the disappearance, regression, or progression of the condition.

Prognostic tests predict the risk of developing a condition in the future. Tests to predict response to therapy are also prognostic. Response to therapy is a type of condition and can be either a beneficial response or adverse response. The term predictive test is often used to refer to the response to therapy. To simplify terms, we use prognostic to refer both to predicting a future condition or predicting a response to therapy.

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review, and alternative sources exist. This evidence review focuses on the clinical validity and clinical utility.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Clinical sensitivity and specificity are 99% for premutation and full variant alleles. Although diagnostic errors can occur due to rare sequence variations, CGG repeat expansion full mutations account for more than 99% of cases of FXS.2 Therefore, tests that measure the CGG repeat region of the FMR1 gene are clinically valid. Tests have been shown to be more than 99% sensitive. Positive results are 100% specific. There are no known forms of fragile X mental retardation protein deficiency that do not map to the FMR1 gene.  

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing. 

The conditions caused by abnormal CGG repeats in the FMR1 gene—FXS, fragile X–associated tremor or ataxia syndrome, and fragile X–associated premature ovarian insufficiency—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. The knowledge that the condition is caused by variants of FMR1 provides important knowledge for offspring and for assessing the risk of disease in subsequent generations.

Also, FXS is associated with a number of medical and behavioral comorbidities.12 Behavioral comorbidities may include attention problems, hyperactivity, anxiety, aggression, poor sleep, and self-injury. Individuals with FXS are also prone to seizures, recurrent otitis media, strabismus, gastrointestinal disturbances, and connective tissue problems. A correct diagnosis can lead to the appropriate identification and treatment of these comorbidities.

Section Summary: Individuals With Characteristics of an FXS or a Fragile X–Associated Disorder
The evidence demonstrates that FMR1 variant testing can establish a definitive diagnosis of FXS and fragile X-related disorders when the test is positive for a pathogenic variant. Following a definitive diagnosis, treatment of comorbid conditions may be improved. At a minimum, providing a diagnosis eliminates the need for further diagnostic workup.

INDIVIDUALS WHO HAVE A PERSONAL OR FAMILY HISTORY OF FXS WHO ARE SEEKING REPRODUCTIVE COUNSELING
Clinical Context and Test Purpose
Premutation alleles (55-200 CGG repeats) 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 the transmission; however, expansion to full mutations has not been reported.

Premutation allele prevalence in whites is approximately 1 in 1,000 males and 1 in 350 females.1,13,14 Full mutations are typically maternally transmitted. The mother of a child with an FMR1 variant is almost always a carrier of a premutation or full mutation. Women with a premutation 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 an intellectual disability and decreased fertility.

The purpose of FMR1 testing in patients who have a personal or family history of FXS is to inform reproductive decision making.

The question addressed in this evidence review is: Does FMR1 testing in this population improve health outcomes?

The following PICOTS were used to select literature to inform this review.

Patients
The relevant populations of interest are:

  • Individuals who have a personal or family history of FXS who are seeking reproductive counseling, including:
    • Individuals seeking reproductive counseling who have a family history of FXS 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 further counseling related to the risk of carrier status.
    • Prenatal testing of fetuses of known carrier mothers.

Interventions
The relevant intervention of interest is testing for FMR1 variant status.  

Comparators
Standard clinical evaluation without genetic testing is currently being used for reproductive decision making.

Outcomes
The general outcome of interest is reproductive decision making.

Timing
The timing of the test is when the individual is making reproductive decisions.

Setting
A number of laboratories can perform testing for the FMR1 variant and methylation status.  

Technically Reliable
Assessment of technical reliability focuses on specific tests and operators and requires review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this evidence review, and alternative sources exist.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

The inheritance patterns of the FMR1 gene have been well characterized, and the penetrance of the fragile X—associated disorders is very high.  

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Hersh and Saul (2011) reported on families with an affected male and whether an early diagnosis would have influenced their reproductive decision making.14 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.  

Section Summary: Individuals Who Have a Personal or Family History of FXS Who Are Seeking Reproductive Counseling
Testing the repeat region of the FMR1 gene in the context of reproductive decision making may include individuals with either a family history of FXS or a family history of undiagnosed intellectual disability, fetuses of known carrier mothers, or 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. DNA testing would accurately identify premutation carriers and distinguish premutation from full mutation carrier women.  

SUMMARY OF EVIDENCE
For individuals who have characteristics of FXS or an FXS-associated disorder, the evidence includes studies evaluating the clinical validity of FMR1 variant testing. Relevant outcomes are test accuracy, test validity, and resource utilization. The evidence demonstrates that FMR1 variant testing can establish a definitive diagnosis of FXS and fragile X—related syndromes when the test is positive for a pathogenic variant. Following a definitive diagnosis, treatment of comorbid conditions may be improved. At a minimum, providing a diagnosis eliminates the need for further diagnostic workup. A chain of evidence supports improved outcomes following FMR1 variant testing. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have a personal or family history of FXS who are seeking reproductive counseling, the evidence includes studies evaluating the clinical validity of FMR1 variant testing and the effect on reproductive decisions. Relevant outcomes are test accuracy, test validity, and changes in reproductive decision making. Testing the repeat region of the FMR1 gene in the context of reproductive decision making may include individuals with either a family history of FXS or a family history of undiagnosed intellectual disability, fetuses of known carrier mothers, or 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. DNA testing would accurately identify premutation carriers and distinguish premutation from full mutation carrier women. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

PRACTICE GUIDELINES AND POSITION STATEMENTS
American College of Medical Genetics and Genomics
The American College of Medical Genetics and Genomics (ACMG) made the following recommendations in 2005 on diagnostic and carrier testing for fragile X syndrome (FXS).2 The purpose of these recommendations was 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 intellectual disability.
  • 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 before 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." 

In the clinical genetics evaluation to identify the etiology of autism spectrum disorders, ACMG recommended testing for FXS as part of the first-tier testing.10 

According to ACMG recommendations, the following is the preferred approach to testing2:

  • "DNA analysis is the method of choice if one is testing specifically for fragile X syndrome (FXS) and associated trinucleotide repeat expansion in the FMR1 gene."
  • "For isolated cognitive impairment, DNA analysis for FXS should be performed as part of a comprehensive genetic evaluation that includes routine cytogenetic evaluation. Cytogenetic studies are critical since constitutional chromosome abnormalities have been identified as frequently or more frequently than fragile X mutations in mentally retarded individuals referred for fragile X testing."
  • Fragile X testing is not routinely warranted for children with isolated attention-deficit/hyperactivity disorder (see Subcommittee on Attention-Deficit/Hyperactivity Disorder, Steering Committee on Quality Improvement, & Steering Committee on Quality Improvement Management, 2011).
  • "For individuals who are at risk due to an established family history of fragile X syndrome, DNA testing alone is sufficient. If the diagnosis of the affected relative was based on previous cytogenetic testing for fragile X syndrome, at least one affected relative should have DNA testing." 
  • "Prenatal testing of a fetus should be offered when the mother is a known carrier to determine whether the fetus inherited the normal or mutant FMR1 gene. Ideally, DNA testing should be performed on cultured amniocytes obtained by amniocentesis after 15 weeks’ gestation. DNA testing can be performed on chorionic villi obtained by CVS at 10 to 12 weeks’ gestation, but the results must be interpreted with caution because the methylation status of the FMR1 gene is often not yet established in chorionic villi at the time of sampling. A follow-up amniocentesis may be necessary to resolve an ambiguous result."
  • "If a woman has ovarian failure before the age of 40, DNA testing for premutation size alleles should be considered as part of an infertility evaluation and prior to in vitro fertilization."
  • "If a patient has cerebellar ataxia and intentional tremor, DNA testing for premutation size alleles, especially among men, should be considered as part of the diagnostic evaluation."

ACMG made recommendations on diagnostic and carrier testing for FXS to provide general guidelines to aid clinicians in making referrals for testing the repeat region of the FMR1 gene. These recommendations included testing of individuals of either sex who have intellectual disability, developmental delay, or autism spectrum disorder, especially if they have any physical or behavioral characteristics of FXS.2

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.15 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 (i.e., ovarian insufficiency or failure or an elevated follicle-stimulating hormone level before age 40).16 The College recommended prenatal diagnostic testing for FXS to known carriers of the fragile X premutation or full mutation.

European Molecular Genetics Quality Network
In 2015, the European Molecular Genetics Quality Network issued best practice guidelines for the molecular genetic testing and reporting of FXS, fragile X‒associated primary ovarian insufficiency, and fragile X‒associated tremor or ataxia syndrome.17 The guidelines recommended, "a method which detects the whole range of expansions when testing relatives (including prenatal diagnosis) in a family with any known fragile X disorder due to expansion." Technical limitations of specific techniques, such as Southern blot and polymerase chain reaction‒based methods, were described.

U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATIONS
Not applicable 

ONGOING AND UNPUBLISHED CLINICAL TRIALS
A search of ClinicalTrials.gov in December 2017 did not identify any ongoing or unpublished trials that would likely influence this review.

References: 

  1. Monaghan KG, Lyon E, Spector EB. ACMG Standards and Guidelines for fragile X testing: a revision to the disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics and Genomics. Genet Med. Jul 2013;15(7):575-586. PMID 23765048
  2. Sherman S, Pletcher BA, Driscoll DA. Fragile X syndrome: diagnostic and carrier testing. Genet Med. Oct 2005;7(8):584-587. PMID 16247297
  3. Grasso M, Boon EM, Filipovic-Sadic S, et al. A novel methylation PCR that offers standardized determination of FMR1 methylation and CGG repeat length without southern blot analysis. J Mol Diagn. Jan 2014;16(1):23-31. PMID 24177047
  4. Gatta V, Gennaro E, Franchi S, et al. MS-MLPA analysis for FMR1 gene: evaluation in a routine diagnostic setting. BMC Med Genet. Aug 05 2013;14:79. PMID 23914933  
  5. Chaudhary AG, Hussein IR, Abuzenadah A, et al. Molecular diagnosis of fragile X syndrome using methylation sensitive techniques in a cohort of patients with intellectual disability. Pediatr Neurol. Apr 2014;50(4):368-376. PMID 24630283
  6. Inaba Y, Schwartz CE, Bui QM, et al. Early detection of fragile X syndrome: applications of a novel approach for improved quantitative methylation analysis in venous blood and newborn blood spots. Clin Chem. Jul 2014;60(7):963-973. PMID 24778142
  7. Lim GX, Loo YL, Mundho RF, et al. Validation of a commercially available screening tool for the rapid identification of CGG trinucleotide repeat expansions in FMR1. J Mol Diagn. May 2015;17(3):302-314. PMID 25776194
  8. Nolin SL, Sah S, Glicksman A, et al. Fragile X AGG analysis provides new risk predictions for 45-69 repeat alleles. Am J Med Genet A. Apr 2013;161A(4):771-778. PMID 23444167
  9. Yrigollen CM, Mendoza-Morales G, Hagerman R, et al. Transmission of an FMR1 premutation allele in a large family identified through newborn screening: the role of AGG interruptions. J Hum Genet. Aug 2013;58(8):553-559. PMID 23739124
  10. Schaefer GB, Mendelsohn NJ. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. May 2013;15(5):399-407. PMID 23519317
  11. Miles JH. Autism spectrum disorders--a genetics review. Genet Med. Apr 2011;13(4):278-294. PMID 21358411
  12. Visootsak J, Kidd SA, Anderson T, et al. Importance of a specialty clinic for individuals with fragile X syndrome. Am J Med Genet A. Dec 2016;170(12):3144-3149. PMID 27649377
  13. Hunter J, Rivero-Arias O, Angelov A, et al. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am J Med Genet A. Jul 2014;164A(7):1648-1658. PMID 24700618
  14. Hersh JH, Saul RA. Health supervision for children with fragile X syndrome. Pediatrics. May 2011;127(5):994-1006. PMID 21518720
  15. Moeschler JB, Shevell M, Committee on G. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. Sep 2014;134(3):e903-918. PMID 25157020
  16. American College of Obstetricians and Gynecologists Committee on Genetics. Committee Opinion No. 691: Carrier screening for genetic conditions. Obstet Gynecol. Mar 2017;129(3):e41-e55. PMID 28225426
  17. Biancalana V, Glaeser D, McQuaid S, et al. EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders. Eur J Hum Genet. Apr 2015;23(4):417-425. PMID 25227148

Coding Section

Codes Number Description
CPT  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)

  88248 

Chromosome analysis for breakage syndromes; baseline breakage, score 50-100 cells, count 20 cells, 2 karyotypes (eg, for ataxia telangiectasia, Fanconi anemia, fragile X) 

ICD-9-CM Diagnosis

299.00-299.01

Autistic disorder code range 

 

315.00-315.9

Specific delays in development code range 

 

317-319

Intellectual disabilities code range 

 

V18.4

Family history of intellectual disabilities 

 

V26.31

Testing of female for genetic disease carrier status 

  V28.89

Other specified antenatal screening 

ICD-10-CM (effective 10/01/15) 

F70-F79 

Intellectual Disabilities code range 

 

F80.0-F80.9 

Specific developmental disorders of speech and language code range 

 

F82 

Specific developmental disorder of motor function 

 

F84.0 

Autistic disorder 

 

Z31.430 

Encounter of female for testing for genetic disease carrier status for procreative management 

 

Z31.440 

Encounter of male for testing for genetic disease carrier status for procreative management 

 

Z81.0 

Family history of intellectual disabilities 

ICD-10-PCS (effective 10/01/15)   

Not applicable. ICD-10-PCS codes are only used for inpatient services. There are no ICD procedure codes for laboratory tests. 

Type of Service 

   

Place of Service 

   

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

Appendix

Appendix Table 1. Categories of Genetic Testing Addressed in Policy No. 20483  

Category Addressed

1. Testing of an affected individual’s germline to benefit the individual

 

1a. Diagnostic

X

1b. Prognostic

 

1c. Therapeutic

 

2. Testing cancer cells from an affected individual to benefit the individual

 

2a. Diagnostic

 

2b. Prognostic

 

2c. Therapeutic

 

3. Testing an asymptomatic individual to determine future risk of disease

 

4. Testing of an affected individual’s germline to benefit family members

 

5. Reproductive testing

 

5a. Carrier testing: preconception

X

5b. Carrier testing: prenatal

X

5c. In utero testing: aneuploidy

 

5d. In utero testing: mutations

 

5e. In utero testing: other

 

5f. Preimplantation testing with in vitro fertilization

 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies and accredited national guidelines. 

"Current Procedural Terminology© American Medical Association.  All Rights Reserved"  

History From 2014 Forward      

01/06/2020 

Annual review, no change to policy intent. Updating coding. 

06/19/2019 

Interim review. Genetic counseling is recommended is replacing Genetic counseling is Medically necessary. No other changes made. 

01/02/2019 

Annual review, no change to policy intent. 

12/19/2018 

Updating with 2019 codes. 

01/31/2018 

Annual review, reformatting policy verbiage for clarity. Also updating background, description, guidelines, rationale and references. 

04/26/2017 

Interim review to align with Avalon quarterly schedule. Updated category to Laboratory. 

09/27/2016 

Updated the word guideline to policy when applicable. No change to policy intent. 

07/07/2016 

Annual review, no change to policy intent. Updating background, description, regulatory status, rationale, references and appendix 1. 

07/21/2015 

Annual review, no change to policy intent. Updated background, description, guidelines, rationale and references. Added coding and appendix 1 

07/29/2014

Annual review. Added related policy. Updated desciption, background, rationale and references. Updated policy verbiage to include that uses other than those discussed are investigational. 


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