Medical Policy
Policy Num: 11.003.046
Policy Name: Genetic Testing for FMR1 Variants (Including Fragile X Syndrome)
Policy ID: [11.003.046] [Ac / B / M+ / P+] [2.04.83]
Last Review: February 20, 2025
Next Review: February 20, 2026
Related Policies:
| Population Reference No. | Populations | Interventions | Comparators | Outcomes |
| 1 | Individuals:
| Interventions of interest are:
| Comparators of interest are:
| Relevant outcomes include:
|
| 2 | Individuals:
| Interventions of interest are:
| Comparators of interest are:
| Relevant outcomes include:
|
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.
For individuals who have characteristics of Fragile X syndrome (FXS) or an FXS-associated disorder, the evidence includes studies evaluating the clinical validity of fragile X mental retardation 1 gene (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, the 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 an 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: 1) individuals with either a family history of FXS or a family history of undiagnosed intellectual disability, 2) fetuses of known carrier mothers, or 3) 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 an improvement in the net health outcome.
Not applicable.
The objective of this evidence review is to evaluate whether fragile X mental retardation 1 gene (FMR1) variant testing improves health outcomes in individuals with conditions or family history consistent with the presence of a pathogenic FMR1 variant (eg, premutation or mutation).
Genetic testing for fragile X mental retardation 1 gene (FMR1) variants may be considered medically necessary for the following populations:
Individuals with characteristics of fragile X syndrome (FXS) 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 FXS who are seeking reproductive counseling, including:
Individuals 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 information on carrier status;
Prenatal testing of fetuses of known carrier mothers.
Genetic testing for FMR1 variants is investigational for all other uses.
Physical and behavioral characteristics of fragile X syndrome (FXS)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.
Detection of CGG triplet repeats in the fragile X mental retardation 1 gene (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 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 (see Spector et al, 2021).
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 (Table PG1). 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 PG2 shows the recommended standard terminology - “pathogenic,” “likely pathogenic,” “uncertain significance,” “likely benign,” and “benign” to describe variants identified that cause Mendelian disorders.
| Previous | Updated | Definition |
| Mutation | Disease-associated variant | Disease-associated change in the DNA sequence |
| 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 |
| 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
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.
See the Codes table for details.
Some Plans may have contract or benefit exclusions for genetic testing.
Benefits are determined by the group contract, member benefit booklet, and/or individual subscriber certificate in effect at the time services were rendered. Benefit products or negotiated coverages may have all or some of the services discussed in this medical policy excluded from their coverage.
According to Law 163 of August 13, 2024 - “Law for the Protection, Security, Integration, Well-being and Comprehensive Development of People with Autism Spectrum Disorders”, insurance providers are obliged to offer coverage for all health interventions scientifically validated as effective for Autism Spectrum Disorders and may not establish limitations regarding age, limit of benefit, or number of visits to a medical services professional, once medical necessity has been established by a licensed physician.
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 the methylation status of the FMR1 gene. Two main approaches are used: polymerase chain reaction (PCR) and Southern blot analysis.
The 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 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.3,4,5,6, 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, Asuragen offers the Xpansion Interpreter® test, which analyzes AGG sequences that interrupt CGG repeats and may stabilize alleles, protecting against expansion in subsequent generations.8,9, 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) (see Regulatory Status).10,
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.
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.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). The Xpansion Interpreter test is available under the auspices of CLIA. Laboratories that offer laboratory-developed tests must be licensed by CLIA for high-complexity testing. Until 2020, the FDA 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.10,11, 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.
This evidence review was created in June 2012 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through November 21, 2024.
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.
Promotion of greater diversity and inclusion in clinical research of historically marginalized groups (e.g., People of Color [African-American, Asian, Black, Latino and Native American]; LGBTQIA (Lesbian, Gay, Bisexual, Transgender, Queer, Intersex, Asexual); Women; and People with Disabilities [Physical and Invisible]) allows policy populations to be more reflective of and findings more applicable to our diverse members. While we also strive to use inclusive language related to these groups in our policies, use of gender-specific nouns (e.g., women, men, sisters, etc.) will continue when reflective of language used in publications describing study populations.
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 4000 males and 1 in 8000 females. In addition to intellectual impairment, patients present with 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 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 is associated with the expansion of the CGG trinucleotide repeat in the fragile X mental retardation 1 (FMR1) gene on the X chromosome. The syndrome 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. Fragile X syndrome 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.
Patients with a premutation (55 to 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. 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. Fragile X-associated premature ovarian insufficiency is characterized by ovarian failure before 40 years of age.
Diagnosis of 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 (Table 1).12, Approximately 1% to 3% of children initially diagnosed with autism are shown to have FXS, with the expansion of the CGG trinucleotide repeat in the FMR1 gene to full mutation length.13,A considerable number of children evaluated for autism have been found to have an FMR1 premutation (55 to 200 CGG repeats).14, Fragile X-associated disorders (fragile X-associated premature ovarian insufficiency and fragile X-associated tremor or ataxia) are associated with an FMR1 premutation (55 to 200 CGG repeats).
| 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 individuals 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 following PICO was used to select literature to inform this review.
The relevant population of interest is:
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 fragile X-associated premature ovarian insufficiency is suspected.
Individuals with neurologic symptoms consistent with fragile X-associated tremor or ataxia syndrome.
The relevant interventions of interest are testing for FMR1 variant and methylation status.
Standard clinical evaluation without genetic testing is used to diagnose FXS or a fragile X-associated disorder.
The general outcomes of interest are an accurate diagnosis of individuals with FXS or fragile X-associated disorders and improved management of the disorder. This test would be performed when characteristics of FXS or fragile X-associated disorders are identified.
For the evaluation of clinical validity of the test, studies that meet the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
Included a suitable reference standard
Patient/sample clinical characteristics were described
Patient/sample selection criteria were described.
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.
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, more effective therapy, or avoid unnecessary therapy or testing.
The conditions caused by abnormal CGG repeats in the FMR1 gene– 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.15, 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.
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, the treatment of comorbid conditions may be improved. At a minimum, providing a diagnosis eliminates the need for further diagnostic workup.
For individuals who have characteristics of Fragile X syndrome (FXS) or an FXS-associated disorder, the evidence includes studies evaluating the clinical validity of fragile X mental retardation 1 gene (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, the 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 an improvement in the net health outcome.
Premutation alleles (55 to 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 1000 males and 1 in 350 females.1,16,17, 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 to 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 individuals who have a personal or family history of FXS is to inform reproductive decision-making.
The following PICO was used to select literature to inform this review.
The relevant population of interest is:
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.
The relevant intervention of interest is testing for FMR1 variant status.
Standard clinical evaluation without genetic testing is currently being used for reproductive decision-making.
The general outcome of interest is reproductive decision-making. The timing of the test is when the individual is making reproductive decisions.
For the evaluation of clinical validity of the test, studies that meet the following eligibility criteria were considered:
Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
Included a suitable reference standard
Patient/sample clinical characteristics were described
Patient/sample selection criteria were described.
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.
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, more effective therapy, or avoid unnecessary therapy or testing.
Hersh and Saul (2011) reported on families with an affected male and whether an early diagnosis would have influenced their reproductive decision-making.17, 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 a second child with a full mutation. LePoulennec et al (2024) reported on pregnancy outcomes in women with FMR1 gene premutations.18,Before the premutations were found, the 63 affected women had 20 live births. Of these 20, 7 children were diagnosed with FXS. After the diagnosis of the gene premutation, these women had 23 pregnancies, 18 of which led to a diagnosis of FXS. The authors concluded that genetic counseling about the possibility of transmitting FXS genes is needed, along with education about the the opportunity to seek preimplantation or prenatal diagnosis.
Testing the repeat region of the FMR1 gene in the context of reproductive decision-making may include: 1) individuals with either a family history of FXS or a family history of undiagnosed intellectual disability, 2) fetuses of known carrier mothers, or 3) 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.
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: 1) individuals with either a family history of FXS or a family history of undiagnosed intellectual disability, 2) fetuses of known carrier mothers, or 3) 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 an improvement in the net health outcome.
The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information’ if they were issued by, or jointly by, a US professional society, an international society with US representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.
In 2005, the American College of Medical Genetics and Genomics (ACMG) made the following recommendations 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 fragile X mental retardation 1 (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.13,
According to the ACMG recommendations, the following is the preferred approach to testing:2,
“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 [chorionic villous sampling] 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.”
The 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,
In 2021, the ACMG released a revised technical standard on laboratory testing for fragile X.12, The authors noted that the new laboratory standards "are in general agreement" with the 2005 ACMG policy statement summarized above.
In 2014 (reaffirmed in 2019), the American Academy of Pediatrics recommended that fragile X testing is performed in any child who presents with global developmental delay or intellectual disability without a specific etiology.19,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).
In 2017 (reaffirmed in 2023), 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 years).20, The College recommended prenatal diagnostic testing for FXS to known carriers of the fragile X premutation or full mutation.
Not applicable.
There is no national coverage determination. In the absence of a national coverage determination, coverage decisions are left to the discretion of local Medicare carriers.
A search of ClinicalTrials.gov in November 2024 did not identify any ongoing or unpublished trials that would likely influence this review.
| Codes | Number | Description |
| CPT | 81243 | FMR1 (fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; evaluation to detect abnormal (eg, expanded) alleles |
| | 81244 | FMR1 (fragile X mental retardation 1) (eg, fragile X mental retardation) gene analysis; characterization of alleles (eg, expanded size and methylation status) |
| ICD-10-CM | E28.310-E28.39 | Primary ovarian failure code range |
| | 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-F84.9 | Pervasive developmental disorders (includes Autism F84.0) |
| | F88 | Other disorders of psychological development |
| | Q99.2 | Other chromosomal abnormalities; Fragile X chromosome (includes fragile X syndrome) |
| | 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 | | 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 | Professional/Outpatient |
| Date | Action | Description |
| 02/20/2025 | Annual Review | Policy updated with literature review through November 21, 2024; reference added. Policy statements unchanged. |
| 11/26/2024 | Policy Revision | A statement regarding P.R. Law 63 for the Protection of People with Autism Spectrum Disorders has been added. |
| 02/13/2024 | Annual Review | Policy updated with literature review through November 20, 2023; no references added. Minor editorialrefinements to policy statements; intent unchanged. |
| 02/18/2023 | Annual Review | Policy updated with literature review through November 13, 2022; no references added. Policy statements unchanged. |
| 02/22/2022 | Annual Review | Policy updated with literature review through November 12, 2021; reference added. Policy statements unchanged. |
| 02/19/2021 | Annual Review | Policy updated with literature review through November 16, 2020; no references added. Policy statements unchanged. |
| 02/21/2020 | Annual Review | Policy updated with literature review through November 11, 2019; no references added. Policy statements unchanged. |
| 01/30/2020 | Annual Review | No changes |
| 01/21/2019 | Updated | Policy updated with literature review through November 1, 2018; no references added. Policy statements unchanged. |
| 01/11/2018 | | |
| 08/12/2015 | | |
| 06/11/2015 | | |
| 06/16/2014 | | |
| 09/17/2013 | |