CurrentCapital BluecrossPolicy MP 2.276

Genetic testing for pathogenic FMR1 variants (including Fragile X syndrome)

This policy governs medical necessity and coverage criteria for genetic testing of the FMR1 gene (including Fragile X syndrome and related disorders) for Capital BlueCross members, specifying populations for whom testing is considered medically necessary and indicating investigational uses.

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for pathogenic FMR1 variants (including Fragile X syndrome)

Policy CodePolicy MP 2.276

Change TypeNo material changes

Effective Date10/01/2025

Next Review DateN/A

Key ActionObtain and document genetic counseling by a clinician experienced in genetic medicine when ordering FMR1 testing for diagnosis or reproductive counseling.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

55-200CGG premutation range

>200Full mutation threshold

3 codesProcedure codes covered

FDA clearedAmplideX status

10/01/2025

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Coverage Criteria

Medically necessary indications

Genetic testing for FMR1 variants is considered medically necessary when ANY of the following patient groups are tested:

ANY of the following

Individuals with characteristics of fragile X syndrome or a fragile X-associated disorder, including: (1) individuals with intellectual disability, developmental delay, or autism spectrum disorder; (2) women with primary ovarian insufficiency under the age of 40 in whom fragile X-associated primary ovarian insufficiency is suspected; (3) individuals with neurologic symptoms consistent with fragile X-associated tremor/ataxia syndrome.
Individuals who have a personal or family history of fragile X syndrome who are seeking reproductive counseling, including: (1) individuals with a family history of fragile X syndrome or a family history of undiagnosed intellectual disability; (2) affected individuals or relatives of affected individuals who have had a positive cytogenetic fragile X test result who are seeking information on carrier status; (3) prenatal testing of fetuses of known carrier mothers.

Medically Necessary Indications — Diagnosis and Reproductive Counseling

Testing for FMR1 variants is covered when medically necessary for diagnosis or reproductive counseling in the following contexts:

ANY of the following

Diagnostic testing to establish a definitive diagnosis of fragile X syndrome (FXS) or fragile X-related syndromes in individuals with compatible clinical features or signs; a positive pathogenic variant establishes diagnosis and can reduce further diagnostic workup.
Carrier testing for individuals with a personal or family history of FXS or undiagnosed intellectual disability who are seeking information to inform reproductive decision making.
Prenatal testing of fetuses of known FMR1 carrier mothers for the purpose of reproductive counseling or pregnancy management.

Examples of investigational / not covered uses include, but are not limited to: population screening of asymptomatic individuals without a relevant personal or family history; fetal diagnostic testing and screening of eggs obtained for in vitro fertilization prior to implantation using certain kits not indicated for those purposes; and any other use outside the enumerated medically necessary indications.

AmplideX® Fragile X Dx and Carrier Screen Kit (Asuragen) has FDA de novo 510(k) classification for diagnosis of FXS in conjunction with family history and clinical signs and symptoms and for carrier testing, but it is not indicated for fetal diagnostic testing, screening of eggs obtained for in vitro fertilization prior to implantation, or stand-alone diagnosis of FXS. Laboratories offering laboratory-developed tests must meet CLIA requirements.

Genetic testing for FMR1 variants for any indications not explicitly listed as medically necessary above is considered investigational due to insufficient evidence of benefit and is therefore not covered.

Indications Considered Medically Necessary

inv-22: Individuals with clinical features of Fragile X syndrome or fragile X-associated disorders (intellectual disability, developmental delay, autism spectrum disorder; women <40 with suspected FXPOI; individuals with tremor/ataxia symptoms).

Clinical features: Individuals with clinical features of Fragile X syndrome or fragile X–associated disorders, including intellectual disability, developmental delay, or autism spectrum disorder.

FXPOI suspicion: Women under age 40 with primary ovarian insufficiency when fragile X–associated primary ovarian insufficiency (FXPOI) is suspected.

FXTAS symptoms: Individuals with neurologic symptoms consistent with fragile X–associated tremor/ataxia syndrome (e.g., intention tremor, ataxia) where FMR1 testing would inform diagnosis or management.

inv-23: Individuals with personal or family history of Fragile X seeking reproductive counseling, carrier status determination, or prenatal testing when mother is a known carrier.

Billing and Diagnostic Codes

Covered when medically necessary (procedure codes)CPTCovered

81243
81244
0378U

Covered when medically necessary (diagnosis/encounter codes)ICD-10Covered

E28.310	Symptomatic premature menopause
E28.319	Asymptomatic premature menopause
E28.39	Other primary ovarian failure
F70	Mild intellectual disabilities
F71	Moderate intellectual disabilities
F72	Severe intellectual disabilities
F73	Profound intellectual disabilities
F79	Unspecified intellectual disabilities
F80.0	Phonological disorder
F80.1	Expressive language disorder

1–10 of 27

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CGG repeat count thresholds — FMR1

Normal (common) rangeFMR1 alleles with CGG repeat counts below approximately 55 repeats are considered within the normal range or common/typical range.

Gray zone (intermediate)Alleles with repeat counts just above the normal range (often described as a gray zone) — borderline/intermediate repeat counts between normal and premutation ranges.

PremutationAlleles with approximately 55–200 CGG repeats (premutation range).

Full mutationAlleles with >200 CGG repeats (full mutation), typically associated with hypermethylation and Fragile X syndrome.

Provider Actions and Operational Guidance

Note

Program/product applicability

This policy applies only to certain programs and products administered by Capital Blue Cross and is subject to benefit variations. Coverage and payment are determined by the member's specific benefit program and eligibility on the date of service. Refer to the FEP PPO Medical Policy Manual for Federal Employee Program members: https://www.fepblue.org/benefit-plans/medical-policies-and-utilization-management-guidelines/medical-policies

Applicability may vary by product and program; always verify member benefits prior to ordering testing.
FEP PPO members: see FEP Medical Policy Manual (link above).

Billing Rule

Coverage for listed procedure codes

Testing for FMR1 variants (listed procedure codes) is covered when medically necessary for indications in this policy. Coverage decisions require confirmation of member benefits and medical necessity.

Eligibility Requirements

Family history supports coverage when testing is sought for diagnosis or reproductive counseling. Specifically, a personal or family history of Fragile X syndrome or a family history of undiagnosed intellectual disability may justify testing to determine carrier status or for reproductive decision making, including prenatal testing of fetuses of known carrier mothers.

Covered indications include testing for individuals with features of Fragile X syndrome or related disorders and for those seeking reproductive counseling. The evidence supports that FMR1 variant testing can establish a definitive diagnosis and inform reproductive decisions, improving net health outcome.

When a relative or an affected individual has a prior positive cytogenetic fragile X test, molecular FMR1 testing is appropriate for relatives or affected individuals seeking clarification of carrier status. DNA-based testing accurately identifies premutation and full mutation alleles and can replace or follow prior cytogenetic testing to provide definitive carrier information for counseling.

Eligibility is determined by clinical indication and whether testing is expected to inform diagnosis or reproductive counseling. The policy supports testing for individuals with clinical features of FXS or fragile X-associated disorders and for those with personal or family history who require carrier information for reproductive decision making.

Background and Clinical Context

Fragile X syndrome (FXS) is caused by expansion of CGG trinucleotide repeats in the FMR1 gene leading to hypermethylation and loss of FMR1 expression. A full mutation is generally defined as >200 CGG repeats, and a premutation is approximately 55–200 repeats. FXS is the most common inherited form of intellectual disability and is associated with autism and other neurologic and connective tissue features; premutation carriers are at risk for fragile X-associated tremor/ataxia syndrome and fragile X-associated primary ovarian insufficiency.

Definitions

Full mutation (FMR1 >200 CGG repeats)

DefinitionExpansion of CGG repeats above 200 in the 5' untranslated region of FMR1 leading to promoter hypermethylation and transcriptional inactivation; causes loss of FMR1 protein and is associated with Fragile X syndrome.

Clinical consequenceAssociated with intellectual disability, developmental problems, and features of Fragile X syndrome; confirms diagnosis when detected.

Diagnostic implicationFull mutation detected by DNA testing establishes a definitive diagnosis of Fragile X syndrome and can prevent further diagnostic workup.

Premutation (FMR1 ~55–200 CGG repeats)

DefinitionAlleles with approximately 55–200 CGG repeats in FMR1; considered premutation range.

Associated risksPremutation carriers may develop fragile X-associated tremor/ataxia syndrome (FXTAS) and, in women, fragile X-associated primary ovarian insufficiency (FXPOI).

Not Covered / Investigational Uses

Use of testing for indications not listed as medically necessary is considered investigational and may be denied. Cytogenetic testing alone is no longer considered an acceptable diagnostic method compared with current DNA-based FMR1 testing methods; providers should use molecular assays (e.g., CGG repeat sizing and methylation testing) when clinically indicated.

Testing performed for uses outside the policy’s listed medically necessary indications is investigational. Cytogenetic testing alone is insufficient compared with DNA testing for the FMR1 repeat region; molecular testing should be used to establish diagnosis or carrier status when indicated.

The AmplideX® Fragile X Dx and Carrier Screen Kit is not indicated for fetal diagnostic testing, for screening of eggs obtained for in vitro fertilization prior to implantation, or as a stand-alone diagnostic assay for Fragile X syndrome according to its FDA-cleared intended use.

Policy History and Revision Notes

2025-08-25Administrative UpdateLatest

Removed Benefit Variations Section and updated Disclaimer.

2025-05-05Consensus Review

No change to policy statement; updated references and coding reviewed with no changes.

2024-11-19Consensus Review

Policy Summary

PayerCapital Bluecross

PolicyGenetic testing for pathogenic FMR1 variants (including Fragile X syndrome)

Policy CodePolicy MP 2.276

Change TypeNo material changes

Effective Date10/01/2025

Next Review DateN/A

Key ActionObtain and document genetic counseling by a clinician experienced in genetic medicine when ordering FMR1 testing for diagnosis or reproductive counseling.

SourceLink

On This Page

Personal or family history: Individuals with a personal or family history of Fragile X who are seeking reproductive counseling or carrier-status information.

Relatives of affected individuals: Affected individuals or relatives of affected individuals who had a positive cytogenetic fragile X test result and who seek molecular testing to determine carrier status or to inform reproductive decisions.

Prenatal testing of fetuses when the mother is a known carrier of an FMR1 pathogenic variant.

inv-24: Diagnosis of FXS in individuals with clinical features or FXS-associated disorders — Testing can establish definitive diagnosis and improve management.

Definitive diagnosis: Testing in individuals with clinical features of FXS or FXS-associated disorders can establish a definitive diagnosis of Fragile X syndrome when a pathogenic FMR1 variant is identified.

Establishing a diagnosis can improve management and eliminate need for further diagnostic workup.

inv-25: Carrier testing for individuals with personal or family history seeking reproductive counseling — Includes identification of premutation carriers and distinction between premutation and full mutation.

Carrier testing for reproductive counseling: Carrier testing is indicated for individuals with a personal or family history of Fragile X who are seeking reproductive counseling; testing identifies premutation carriers (approximately 55–200 CGG repeats) and distinguishes premutation from full mutation (>200 repeats) to inform reproductive risk and counseling.

Covered procedure codes when medically necessary include CPT/HCPCS and other codes as listed in the policy coding section (e.g., 81243, 81244, 0378U).
Providers must document the medical indication that meets policy criteria.
Coverage for specific codes is subject to member benefit limitations and may vary by product.

Documentation Required

Claims and documentation

Payment of claims is subject to the member's benefit program, eligibility on the date of service, and a determination that services are medically necessary and appropriate. Final processing of a claim is based upon the terms of the contract that applies to the member's benefit program, including limitations and exclusions. Providers or members with questions should contact Capital Blue Cross Provider Services or Member Services.

Verification of eligibility and benefits is required prior to testing.
Medical necessity must be documented in the medical record and submitted with claims as required.
A policy determination does not guarantee coverage or payment.

Documentation Required

Genetic counseling documentation

Genetic counseling by an individual with experience and expertise in genetic medicine and genetic testing methods is recommended in most cases when testing for an inherited FMR1 condition is considered. Counseling helps patients understand risks, benefits, and potential family implications and may influence testing decisions.

Document that genetic counseling was provided or offered and by whom (provider specialty/credentials).
Counseling is particularly recommended for individuals undergoing testing for reproductive decision making or carrier assessment.

Note

Testing strategy

Testing strategy: Detection of CGG triplet repeats and methylation status can be performed sequentially or in parallel. Sequential testing typically performs CGG repeat sizing first; if a large number of repeats (for example, >55) is detected, reflex methylation testing may be performed. Parallel methods (e.g., methylation-specific PCR) can determine both repeat size and methylation status in one workflow.

When ordering, indicate whether reflex methylation testing is expected if repeat expansion is identified.
Be aware of assay limitations: standard PCR may fail to amplify very large expansions (>100–150 CGG repeats); Southern blot or alternative methods may be required to determine full mutation and methylation status.
Laboratories may offer combined assays (triplet repeat-primed PCR with methylation analysis) — confirm test methodology and turnaround time prior to ordering.

Denial Risk

Eligibility and medical necessity

Eligibility and medical necessity: Genetic testing for FMR1 variants is considered medically necessary for individuals meeting the policy indications (e.g., individuals with intellectual disability, developmental delay, autism spectrum disorder, suspected fragile X–associated primary ovarian insufficiency in women <40, individuals with neurologic signs of fragile X–associated tremor/ataxia, and individuals/families seeking reproductive counseling). Testing performed for other uses is investigational and may be denied.

Ensure patient meets one or more medically necessary indications prior to ordering and document clinical findings supporting the indication.
Examples of covered clinical diagnoses include intellectual disability, developmental disorders, autism spectrum disorder, primary ovarian insufficiency, family history of fragile X, and prenatal testing for fetuses of known carrier mothers.
Testing for indications not specified in the policy is investigational; obtain prior authorization if required and document the rationale for testing.

Clinical useIdentification of premutation alleles is important for reproductive counseling and risk assessment for associated adult-onset disorders.

FMR1 variant testing (CGG repeat sizing and related assays)

Test descriptionDNA testing of the FMR1 gene repeat region to quantify CGG trinucleotide repeat size and identify premutation and full mutation alleles.

PurposeUsed to establish definitive diagnosis of Fragile X syndrome, identify premutation carriers, and support reproductive counseling and carrier detection.

Testing methodsIncludes CGG repeat sizing (PCR and/or Southern blot) and may include methylation testing when indicated; combined or sequential strategies are acceptable.

No change to policy statement; updated references and coding reviewed with no changes.

2023-10-18Consensus Review

No change to policy statement; updated references and updated references and coding reviewed with no changes.

2023-03-16Administrative Update

New CPT code 0378U added, effective 04/01/2023.

2022-02-21Consensus Review

Removed ICD-10 code F84.2; updated cross references, FEP, background, and references.

2021-07-19Consensus Review

Updated FEP, background, and references; no changes to coding.

2020-11-20Consensus Review

Policy statement unchanged; background updated and references reviewed.