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    v1.0.28
    OpenPayerPolicy UpdatesGenetic & Molecular TestingAmbetter Nevada Genetic Testing Coverage Update | …
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    ModifiedAmbetter NevadaPolicy N/A

    Genetic Testing: Multisystem Genetic Conditions

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    Defines coverage and coding guidance for exome, genome, multigene panels, chromosomal microarray, and mitochondrial testing to diagnose suspected multisystem genetic disorders for providers submitting claims to Ambetter Nevada.

    Policy Summary
    PayerAmbetter Nevada
    PolicyGenetic Testing: Multisystem Genetic Conditions
    Policy CodePolicy N/A
    Change TypeCriteria revised and additions consolidated (NF1/NF2, mitochondrial, PIK3CAcoding examples updated)
    Effective DateN/A
    Next Review DateN/A
    Key ActionInclude documentation of guideline-based clinical criteria and prior nondiagnostic testing when submitting prior authorization requests.
    SourceLink
    POLICY UPDATE CHANGES

    Updated NF2-related schwannomatosis criteria: added explicit genetic and adult clinical criteria including bilateral vestibular schwannomas, unilateral vestibular schwannoma with additional findings, and multiple meningiomas with specified accompanying findings.

    Multiple specific criteria and age/feature wording edits across syndrome-specific sections (e.g., Angelman/Prader-Willi, Beckwith-Wiedemann/Russell-Silver, Fanconi anemia, Fragile X, NF1, PIK3CA, Noonan/RASopathies).

    NF1 criteria were revised to add specific clinical feature enumerations (e.g., six or more café-au-lait macules; freckling; optic glioma; Lisch nodules; distinctive osseous lesion) and to reference NF1 sequencing/deletion/duplication testing.

    PIK3CA sequencing criteria modified to require 'at least one' clinical feature or imaging finding and removed deletion/duplication testing from criteria.

    Criteria for Mitochondrial Genome Sequencing, Deletion/Duplication, and nuclear gene panels were added from a previously separate policy; several connective tissue and rapid/standard exome/genome criteria were incorporated.

    multipletest categories
    manycodes referenced
    pre/postcounseling advised
    ~20sections updated
    severalnot supported items
    semi-annualreview cadence

    Coverage Criteria and Medical Necessity

    Summary of Recent Criteria Changes

    Summary of recent criteria changes — consolidated list of substantive updates made during the most recent policy revision cycle.

    Renamed and reorganized several disorder-specific criteria sections to align with consolidated policy structure (e.g., replacing previous policy names with Concert Genetic Testing: Multisystem Genetic Conditions).
    Added and clarified criteria for Mitochondrial Genome Sequencing, Deletion/Duplication, and/or Nuclear Gene Panels (moved from prior 'Metabolic, Endocrine, and Mitochondrial Disorders' policy).
    Added connective tissue disorder criteria previously in the 'Aortopathies and Connective Tissue Disorders' policy: Classic Ehlers-Danlos Syndrome (cEDS) multigene panel; COL3A1 sequencing/deletion-duplication for vEDS; Comprehensive connective tissue disorders multigene panel; Loeys-Dietz syndrome multigene panel; FBN1 sequencing and/or deletion/duplication analysis; and other rare connective tissue disorders.
    Added exome/genome sequencing related criteria previously in the 'Exome and Genome Sequencing for the Diagnosis of Genetic Disorders' policy: Rapid exome sequencing; rapid genome sequencing; reanalysis of exome or genome sequencing data; standard exome sequencing; and standard genome sequencing.
    Policy Summary
    PayerAmbetter Nevada
    PolicyGenetic Testing: Multisystem Genetic Conditions
    Policy CodePolicy N/A
    Change TypeCriteria revised and additions consolidated (NF1/NF2, mitochondrial, PIK3CAcoding examples updated)
    Effective DateN/A
    Next Review DateN/A
    Key ActionInclude documentation of guideline-based clinical criteria and prior nondiagnostic testing when submitting prior authorization requests.
    SourceLink
    On This Page
    Coverage Criteria and Medical NecessityIndications Where Testing Is CoveredProvider Requirements, Prior Authorization, and DocumentationCoding Table and Test IdentifiersTests and Indications Not SupportedDefinitions and Clinical TermsPolicy Updates and Material Changes
    Updated NF1 and NF2 sections: replaced prior 'Legius Syndrome SPRED1' reference with NF1 updates; clarified NF1 diagnostic criteria and added additional NF2-related schwannomatosis criteria and reorganized NF2 clinical criteria (including adult and pediatric distinctions).
    Updated Noonan Spectrum Disorders/RASopathy section: broadened language to '/RASopathy' and clarified that at least one listed clinical feature is required for panel testing; removed minimum gene list to reflect limited rationale for mandated gene sets.
    Revisions to PIK3CA criteria: adjusted imaging and clinical feature language (e.g., replaced 'two or more' phrasing with 'at least one' for certain brain imaging or clinical features) and emphasized need for testing multiple tissue types due to mosaicism.
    TSC criteria refined to align with current consensus: clarified major and minor features (e.g., 'Two or more subependymal nodules'); reiterated benefit of genetic diagnosis prior to full clinical manifestation for surveillance.
    Chromosomal microarray (CMA) language updated to reflect 2021 focused revisions and reaffirmations: CMA retained as first-tier testing for global developmental delay/intellectual disability, autism spectrum disorder, multiple congenital anomalies, and certain short stature indications; investigational language clarified for isolated speech/language delay.
    Angelman and Prader-Willi testing strategy clarified and reordered recommended stepwise testing (methylation analysis first, followed by deletion, UPD, then imprinting defect analysis where applicable).
    Beckwith-Wiedemann and Russell-Silver syndrome criteria incorporated and clarified (tiered features and NH-CSS scoring referenced).
    Changed policy phrasing from 'investigational' to 'current evidence does not support…' for several sections to standardize statement language across the document.
    Moved criteria for Known Familial Variant Analysis for multisystem inherited disorders into the separate policy 'Genetic Testing: General Approach to Genetic and Molecular Testing' to centralize familial-variant decision rules.
    Removed or consolidated outdated single-gene minimum lists for several multigene panels (e.g., Noonan, Fanconi anemia) where limited rationale exists for rigid gene lists; emphasized phenotype-driven panel selection or comprehensive testing approaches.
    Minor wording edits for clarity across multiple sections and updates to coding/reference tables and background rationale; coding lists and references were reviewed and updated where applicable.
    Administrative updates: updated policy title to reflect V2.2024 version, performed semi-annual review, and recorded revision history and reference consolidations in the References/Revision notes.

    Indications Where Testing Is Covered

    Provider Requirements, Prior Authorization, and Documentation

    Billing Rule

    Coding & prior authorization guidance

    Providers must reference the most up-to-date coding guidance and payer-specific billing rules before submitting claims. Inclusion or exclusion of example CPT/HCPCS codes in this policy does not guarantee coverage. Claims submitted with outdated, incorrect, or mismatched codes (including test identifiers) may be denied or result in reimbursement delays. Use the Policy Reference Table test identifiers when available (for example, Genomic Unity Exome Analysis 81415/81416) and ensure coding is consistent with the payer’s current fee schedule and reference table.

    • Verify CPT/HCPCS codes and payer test identifiers prior to claim submission
    • Claims with coding/test examples inconsistent with the Policy Reference Table may be denied
    Prior Authorization

    Prior authorization required for CHD7 testing

    Prior authorization is required when ordering CHD7 sequencing and/or deletion/duplication analysis for suspected CHARGE syndrome. Documentation submitted with the authorization request should list the specific clinical features that meet the CHD7 criteria (at least two listed major features).

    • Affected CPT examples: 81407, 81479
    • Provide clinical features (e.g., coloboma, choanal atresia, cranial nerve anomalies) to justify testing
    Prior Authorization

    Exome/Genome sequencing authorization

    Exome or genome sequencing (ES/GS) may require prior authorization when requested outside the policy’s specified indications (e.g., CA/DD/ID with onset criteria). ES/GS is supported per guideline-based criteria (ACMG, NSGC, PLUGS) — particularly for congenital anomalies, developmental delay/intellectual disability with onset <18 years, critically ill neonates/infants, or when a tiered testing approach has been exhausted. Prior authorization should include the indication, prior testing performed, and rationale for ES/GS over targeted testing.

    • ACMG supports ES/GS as first- or second-line for congenital anomalies or ID/DD in many cases
    • Provide prior test results and justification when requesting ES/GS
    • Rapid ES/GS: reserve for situations where it’s more efficient and economical than serial testing
    Documentation Required

    Justify testing with guideline-based clinical criteria

    Prior authorization requests for molecular testing must justify the test by documenting guideline-based clinical criteria, specific clinical features, and relevant family history. Failure to document that the proband meets the clinical diagnostic threshold or to include required prior testing may lead to denial.

    • Include specific clinical findings used to meet criteria (e.g., Tier 1/2 findings for BWS, major/minor features for TSC)
    • Attach relevant prior diagnostic testing results (imaging, laboratory, tumor testing) and three‑generation family history when pertinent
    Prior Authorization

    Prior authorization for NF sequencing

    Prior authorization is required for NF-related sequencing and deletion/duplication analyses. Authorization requests must demonstrate that the member meets the payer’s clinical criteria for NF1 or NF2 (or has a tumor tissue pathogenic variant for NF2) — provide the specific diagnostic features or affected biological parent information for NF1 and tumor testing results or age-specific clinical features for NF2.

    • NF1 criteria examples: six or more café-au-lait macules, two or more neurofibromas or one plexiform neurofibroma, axillary/inguinal freckling, optic glioma, Lisch nodules, distinctive osseous lesions, or an affected biological parent
    • NF2 authorization: provide tumor tissue pathogenic variant when available or clinical findings consistent with NF2 criteria (bilateral vestibular schwannomas, specified combinations of tumors)
    Prior Authorization

    Prior authorization must follow revised criteria and updated codes

    Prior authorization submissions must follow the revised clinical criteria and use updated codes/test identifiers reflected in the Policy Reference Table. Tests ordered using outdated code references or without adherence to the revised criteria may be denied.

    • Use updated Policy Reference Table identifiers (e.g., Genomic Unity Exome Analysis 81415/81416)
    • Do not rely on superseded CPT/code examples in older documents
    Denial Risk

    Mitochondrial testing limited to listed indications

    Mitochondrial genome sequencing, deletion/duplication testing, and nuclear gene panels are limited to the listed clinical indications (for example: ptosis, external ophthalmoplegia, proximal myopathy, exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, diabetes mellitus, fluctuating encephalopathy, seizures, migraine, stroke-like episodes, ataxia, spasticity, chorea, or recurrent pregnancy loss). Tests for other indications are not supported and will be denied.

    • Conventional biochemical studies (plasma/CSF lactate, ketones, plasma acylcarnitines, urinary organic acids) must be completed and nondiagnostic before molecular mitochondrial testing
    • If blood testing is nondiagnostic and clinical suspicion remains high, consider mtDNA testing from alternate tissues (e.g., muscle, urine) due to heteroplasmy
    Denial Risk

    CMA exclusion and documentation

    Chromosomal microarray (CMA) is considered medically necessary for DD/ID, ASD, multiple congenital anomalies, and short stature as specified — but is not supported for isolated speech/language delay or other unlisted indications. Prior authorization and documentation must reflect the appropriate indication; tests for excluded indications will be denied.

    • CMA denied for isolated speech/language delay and other unsupported indications
    • Document the specific clinical indication (e.g., nonsyndromic DD/ID, ASD, multiple congenital anomalies, idiopathic short stature) when requesting CMA
    Denial Risk

    TSC testing denial trigger and documentation

    TSC1/TSC2 sequencing and/or deletion/duplication analysis requires documentation that the member meets the payer’s listed major or minor clinical diagnostic criteria (e.g., three or more angiofibromas, cardiac rhabdomyoma, cortical tubers, hypomelanotic macules, renal angiomyolipoma, SEGA, etc.). Genetic testing is medically necessary when these criteria are met; testing for other indications is not supported.

    • Provide the specific major and/or minor features used to meet the clinical diagnostic threshold
    • Include family history and three-generation pedigree when relevant
    Denial Risk

    NF1 testing denial trigger and documentation

    NF1 sequencing/deletion-duplication testing is medically necessary only when the listed diagnostic features are present or when an affected biological parent meets NF1 criteria. Authorization should include documentation of the specific NF1 diagnostic features or the affected parent’s clinical/genetic diagnosis. Testing without these criteria is not supported.

    • If testing to confirm diagnosis before clinical criteria are met (e.g., young child with only café-au-lait macules), document rationale and family preferences
    • Include previous genetic testing results if available
    Denial Risk

    NF2 testing denial trigger and documentation

    NF2 sequencing/deletion-duplication testing is medically necessary only when tumor or specified clinical criteria are met (e.g., tumor tissue pathogenic variant, bilateral vestibular schwannomas, combinations of schwannomas/meningiomas/ependymomas/cataracts). Provide tumor testing results if available and document clinical features per NF2 criteria; testing outside these criteria is not supported.

    • Include tumor tissue pathogenic variant results when present
    • For adults/children, document the specific combination of clinical findings that meet NF2 criteria
    Denial Risk

    Autism/ID panel investigational — justification required

    Autism/ID multigene panel testing has insufficient evidence to support routine use. Prior authorization requests for Autism/ID panels must provide strong justification referencing guideline-based criteria or consider alternative recommended tests (CMA, fragile X, Rett testing, or ES/GS where appropriate). Lack of supporting evidence or failure to justify panel use may result in denial.

    • AAP and AACAP do not endorse routine Autism/ID multigene panels; consider CMA, fragile X, and ES/GS per guidelines
    • Provide rationale why panel testing is preferred over guideline-recommended alternatives
    Documentation Required

    Genetic counseling documentation

    Document that pre-test and post-test genetic counseling was offered and, when possible, include patient preferences about secondary/incidental findings (opt-in/opt-out). Authorization requests should note whether counseling occurred and whether the patient consents to receive secondary findings.

    • Include counseling notes or a statement that counseling was offered and any decisions about secondary findings
    • Counseling documentation supports informed decision-making and may be requested during review
    Documentation Required

    Pre‑testing biochemical and diagnostic studies for mitochondrial testing

    For mitochondrial testing, demonstrate that conventional biochemical and diagnostic studies were completed and nondiagnostic prior to authorization. Provide results of plasma or CSF lactate concentrations, ketone bodies, plasma acylcarnitines, urinary organic acids, and any relevant imaging or electrophysiologic testing.

    • List completed biochemical tests and their results showing nondiagnostic findings
    • Document additional diagnostic studies (MRI, ECG, EMG, exercise testing) that were completed and nondiagnostic
    Documentation Required

    Clinical feature documentation for FBN1 testing

    When requesting FBN1 sequencing and/or deletion/duplication analysis for suspected Marfan syndrome, include clinical feature documentation such as aortic root Z-score (standardized for age/body size), presence of ectopia lentis, or a computed systemic score (with component findings) supporting a systemic score ≥7.

    • Provide measured aortic root Z-score and method/reference used for calculation
    • Document presence/absence of ectopia lentis and each systemic score component used to reach the threshold
    Documentation Required

    TSC documentation

    When requesting TSC testing, include documentation of the major/minor clinical features used to meet diagnostic criteria (definite TSC = 2 major features or 1 major + 2 minor; possible TSC = 1 major or 2 minor). Family history and a three-generation pedigree should be provided when relevant.

    • List which major and/or minor features are present and any supportive imaging or pathology reports
    • If genetic testing identifies a pathogenic TSC1/TSC2 variant, note implications for surveillance
    Documentation Required

    NF1 documentation

    For NF1 testing requests, document the presence of NF1 diagnostic features (e.g., café-au-lait macules, neurofibromas, freckling, optic glioma, Lisch nodules, osseous lesions) or provide evidence of an affected biological parent. Include prior genetic test results if available.

    • Specify which NF1 diagnostic features are present and provide clinical exam or imaging evidence
    • If testing is being requested before clinical criteria are met, explain rationale and include family preference
    Documentation Required

    NF2 documentation

    For NF2 testing, provide tumor testing results when available and document clinical features consistent with NF2 diagnostic criteria (e.g., bilateral vestibular schwannomas, combinations of meningiomas, schwannomas, ependymomas, or characteristic cataracts). Family history should be included when relevant.

    • Attach tumor tissue testing reports if a pathogenic variant was previously identified
    • Detail the age at onset and combination of tumors/clinical findings used to meet criteria
    Documentation Required

    Mitochondrial testing documentation

    When ordering mitochondrial sequencing or panels, document the tissue source for mtDNA testing (blood vs. other tissue such as muscle or urine) and any prior nondiagnostic testing. Explain tissue selection rationale especially in the setting of suspected heteroplasmy.

    • If blood testing was nondiagnostic and suspicion remains, indicate alternate tissue tested (e.g., muscle, urine) and provide results
    • Describe prior non-diagnostic molecular or biochemical testing
    Documentation Required

    Clinical features and family history

    Include specific clinical features and family history used to justify testing on authorization requests (for example, Tier 1/2 findings for Beckwith-Wiedemann Syndrome, family members with suggestive features, or consanguinity). Clear documentation of the proband’s phenotype and relevant relatives expedites review.

    • Provide a three-generation pedigree when available
    • List specific phenotype features that meet policy criteria
    Documentation Required

    Clinical findings documentation

    Authorization requests should include documentation supporting the presence of specified clinical findings (e.g., bilateral vestibular schwannomas, unilateral vestibular schwannoma with additional tumors) used to meet policy criteria. Attach imaging, pathology, operative, or specialist notes as available.

    • Provide imaging or pathology reports that document tumor types and locations
    • Supply specialist clinic notes (neurotology, neurosurgery, genetics) when available
    Prior Authorization

    Sequential, tiered testing approach and reflex to comprehensive testing

    Follow a sequential and tiered testing strategy where specified by the policy. For chromosome 15 imprinting disorders (Angelman/Prader-Willi), begin with SNRPN/UBE3A methylation analysis; if normal, proceed to deletion analysis of 15q11-q13, then UPD analysis, and finally imprinting defect analysis as indicated. For hearing loss and other phenotypes, start with comprehensive gene panels unless phenotype clearly indicates targeted testing; reflex to broader NGS panels or ES/GS if targeted testing is negative but clinical suspicion persists.

    • Angelman/Prader-Willi recommended sequence: methylation → deletion analysis → UPD analysis → imprinting defect analysis
    • Hearing loss: use tiered approach — start with gene panel unless syndromic features suggest ES/GS
    • Reflex to broader testing (NGS panel or ES/GS) when targeted tests are non-diagnostic and phenotype warrants further workup

    Coding Table and Test Identifiers

    Referenced CPT/HCPCS/U codes in policy reference tablemixed
    81415Exome sequencing, proband or trio (as referenced for Standard and Rapid Exome Sequencing)
    81416Exome sequencing, with parental samples (comparator) (referenced)
    81417Reanalysis of exome/genome data (referenced)
    81425Genome sequencing (standard) (referenced)
    81426Genome sequencing (comparator) (referenced)
    0212UProband whole genome analysis (vendor-specific U-code referenced)
    0213UComparator whole genome analysis (vendor-specific U-code referenced)
    0265UWhole genome sequencing (vendor-specific U-code referenced)
    0094URapid whole genome sequencing (vendor-specific U-code referenced)
    0425URapid whole genome sequencing comparator (vendor U-code referenced)
    1–10 of 22
    1/3
    Panels and multigene panel codesCPT
    81410Comprehensive connective tissue disorder panel (referenced)
    81411Connective tissue multigene panel (referenced)
    81400Sequencing (other) referenced for connective tissue disorders
    81401Sequencing (other) referenced (used in imprinting/11p15 analyses)
    81402Sequencing (other/unlisted) referenced
    81404Sequencing (referenced)
    81405Sequencing (referenced for Loeys-Dietz)
    81406Sequencing (referenced)
    81407Sequencing (referenced)
    81403Sequencing (referenced)
    Neurodevelopmental and CMA codesmixed
    81228Chromosomal microarray analysis (CMA) for developmental delay/ID/ASD/congenital anomalies
    S3870SNP microarray (referenced)
    81470Autism/ID panel (referenced)
    81471Autism/ID panel (referenced)
    81185Targeted deletion/duplication testing (referenced)
    81236Panel code referenced
    81302Panel code referenced
    81321Panel code referenced
    0156UVendor-specific panel U-code (referenced)
    Examples of CPT codes citedCPT
    81407Exome or large-scale sequencing code listed for CHD7 sequencing
    81479Unlisted molecular pathology procedure (used here for CHD7 deletion/duplication)
    Covered/Recommended Tests (examples referenced)mixed
    No codes listed
    Referenced test types (no explicit codes in excerpt)mixed
    not listedThis document section references testing types (e.g., sequencing and/or deletion/duplication analysis, methylation analysis, repeat expansion analysis) but does not list CPT/HCPCS/ICD codes in this excerpt.
    Referenced genetic CPT codes (removed/revised)CPT
    81408Previously referenced code for NF1/NF2 sequencing (removed/replaced in revisions)
    Referenced CPT-like codesCPT
    81408Referenced as sequencing/deletion/duplication code associated with NF1 (document notes 81408 is considered medically necessary in specified circumstances).
    Exome Analysis examplesCPT
    81415Genomic Unity Exome Analysis - Proband (Variantyx) (replaced earlier example entries).
    81416Genomic Unity Exome Analysis - Comparator (Duo or Trio) (Variantyx) (replaced earlier example entries).
    Genetic counseling
    RequirementPre-test and post-test genetic counseling is strongly advised; counseling should include discussion of potential secondary/incidental findings and offer an option to opt out of receiving secondary findings.
    DocumentationDocument that counseling was offered, patient preferences about secondary findings were elicited, and a plan for returning results was formulated.
    Who should counselCounseling should be provided by clinicians knowledgeable in genetics (genetic counselors or appropriately trained providers) as implied by guideline recommendations.
    TimingCounseling should occur prior to testing (pre-test) and after results are available (post-test) to support informed decision-making and family implications.
    Marfan aortic root Z-score
    ThresholdAortic root enlargement defined as Z-score of 2 or greater qualifies as an indication for FBN1 testing.
    Alternate criteriaEctopia lentis or a systemic score ≥7 are other indications for FBN1 sequencing/deletion-duplication.
    Measurement noteAortic size must be standardized to age and body size for accurate interpretation (Z-score >2.0 indicates ≥95th percentile).
    Chromosomal microarray indication: short stature
    IndicationChromosomal microarray (CMA) is indicated for individuals with short stature as one of listed indications for CMA.
    Numeric cutoffNo numeric short stature cutoff is provided in this policy section; refer to clinical resources (e.g., ACMG/ACMG focused guidance) for specific short stature definitions.
    ContextCMA is first-tier for DD/ID, ASD, multiple congenital anomalies, or short stature when clinically appropriate.
    Aortic root enlargement Z-score
    ThresholdAortic root enlargement qualifying for Marfan/FBN1 testing is defined as Z-score >2.0.
    InterpretationZ-score should be standardized to age and body size; Z-score >2.0 corresponds to ≥95th percentile.
    DocumentationRecord the aortic root Z-score in prior-auth/clinical documentation when requesting testing.
    Macrosomia
    DefinitionMacrosomia is noted using cutoff centiles (commonly >90th or >97th centile) in Beckwith-Wiedemann Syndrome diagnostic criteria.
    UseMacrosomia (>90th or >97th centile) is a Tier 1 BWS feature that can support molecular testing when present with other criteria.
    AssessmentUse prenatal and postnatal growth charts/studies to determine centile status for macrosomia documentation.
    Netchine-Harbison SRS diagnostic threshold (NH-CSS)
    Diagnostic thresholdNetchine-Harbison SRS diagnostic threshold: 4 of 6 NH-CSS criteria required for diagnosis (some rare individuals with 3 of 6 have had molecular confirmation).
    ExceptionIndividuals with only 3 of 6 criteria have occasionally had positive molecular findings, but 4/6 is the policy diagnostic threshold.
    ApplicationDocument which NH-CSS features are present when requesting molecular testing for SRS.
    Age for Global Developmental Delay diagnosis
    Age thresholdGlobal Developmental Delay (GDD) is diagnosed in children under age 5 with delays in at least two developmental domains.
    DomainsDomains include communication, gross/fine motor, cognition, social-emotional, or adaptive skills.
    Implication for testingGDD under age 5 supports diagnostic testing pathways (e.g., CMA first-line; ES/GS per guidelines), and documentation of delays in ≥2 domains should be provided.
    NF1 diagnostic feature counts
    Examples of diagnostic featuresNF1 diagnostic feature counts include: six or more café‑au‑lait macules; two or more neurofibromas or one plexiform neurofibroma; axillary/inguinal freckling; optic glioma; two or more Lisch nodules; and distinctive osseous lesion (e.g., sphenoid dysplasia or tibial pseudarthrosis).
    Family historyPresence of an affected biological parent who meets diagnostic criteria qualifies for testing in lieu of full phenotypic enumeration.
    Sensitivity noteA negative NF1 genetic test does not absolutely exclude diagnosis (approximate sensitivity ~95%); document clinical criteria when requesting testing.

    Tests and Indications Not Supported

    The codes listed in policy tables and examples are provided for reference only. Inclusion or exclusion of a code in these lists does not ensure payment or coverage. Providers must confirm covered services and applicable coding rules with the payer before ordering or billing.

    Genetic testing performed solely to evaluate for hypermobile Ehlers‑Danlos syndrome (hEDS) is considered investigational and is not covered. The policy notes that hEDS diagnosis relies on clinical criteria and family history and that no validated causative gene(s) have been identified for hEDS.

    Use of autism spectrum disorder/intellectual disability multigene panels is not supported for all indications. The policy states that current evidence does not support routine use of ASD/ID panels for broad diagnostic application and references professional society guidance recommending alternative first‑line tests (e.g., CMA, Fragile X, or targeted approaches where appropriate).

    Sequencing and deletion/duplication testing for TSC1/TSC2, NF1, and NF2 are medically necessary only when the policy's specified clinical diagnostic criteria are met. Testing for these genes when clinical criteria are not met is not supported and may be denied.

    Concert note and guideline review found insufficient evidence to support routine use of Developmental Delay/Intellectual Disability and Autism multigene panels for all indications. As a result, such panels are not covered except where specific policy criteria or professional guidance support use.

    Requests for genetic testing when the proband does not meet the clinical diagnostic criteria and there is no relevant family history are not indicated by the policy. Testing in the absence of supportive clinical features or family history is not covered for the disorders and genes enumerated in this policy.

    Several prior investigational determinations and numeric code references were revised in this update. Where earlier language or codes previously indicated investigational status, the policy now provides explicit coverage logic or exclusion statements; recent revisions may alter prior investigational determinations and specific exclusions apply as stated in the full policy.

    Certain conditions and test examples were removed from this policy window and are addressed in other policies or were corrected as reference‑table errors. Providers should follow the current policy reference table and related policies for tests moved or removed from this document.

    Definitions and Clinical Terms

    This policy addresses the use of broad and targeted genetic tests — including exome and genome sequencing, mitochondrial genome sequencing, multigene panels, and chromosomal microarray — to diagnose suspected genetic disorders that affect multiple body systems. Coverage depends on the specific test and whether the member meets the disorder‑specific clinical criteria described in the policy.

    Broad tests for multisystem genetic conditions
    DefinitionBroad tests for multisystem genetic conditions include exome sequencing (ES), genome sequencing (GS), large multigene panels, and mitochondrial genome sequencing intended to evaluate genetic disorders affecting multiple organ systems.
    When to useES/GS and broad panels are recommended for congenital anomalies, unexplained DD/ID, or when professional guidelines indicate; rapid ES/GS supported for acutely ill infants when results will impact management.
    Mitochondrial specificsMitochondrial testing should use NGS of the mtDNA genome and may include mtDNA deletion/duplication and nuclear gene panels; consider alternate tissues for heteroplasmy detection.
    Marfan systemic score
    Systemic score useA Marfan systemic score is a points-based score where a total of 7 or higher supports FBN1 testing and contributes to diagnostic considerations.
    Score componentsExamples of scored features include wrist/thumb signs, pectus deformities, hindfoot deformity, pneumothorax, dural ectasia, scoliosis, reduced elbow extension, facial features, skin striae, myopia, mitral valve prolapse, and others (see GeneReviews/marfan.org for full list and point values).
    Diagnostic logicFBN1 pathogenic variant plus either aortic root enlargement (Z-score >2.0), ectopia lentis, or systemic score ≥7 establishes diagnosis in a proband.
    Netchine-Harbison clinical scoring system (NH-CSS)
    NH-CSS definitionThe Netchine-Harbison clinical scoring system (NH-CSS) comprises six clinical features used to evaluate Russell‑Silver syndrome; the policy requires four of six criteria for diagnosis, though some rare individuals with 3/6 have had molecular confirmation.
    NH-CSS featuresFeatures include small for gestational age, postnatal growth failure, relative macrocephaly at birth, frontal bossing, body asymmetry, and feeding difficulties/low BMI or need for feeding support.
    DocumentationSpecify which NH-CSS features are present when requesting molecular testing for SRS.
    Global Developmental Delay (GDD)
    DefinitionGlobal Developmental Delay (GDD) is significant delay (≥2 standard deviations below the mean) in at least two developmental domains and is used for children under age 5.
    DomainsDomains include gross/fine motor, speech/language, cognition, social/personal, and activities of daily living or adaptive skills.
    Testing implicationGDD in a child under age 5 supports first-line diagnostic testing such as chromosomal microarray and consideration of ES/GS per guidelines; document delays in ≥2 domains for prior authorization.
    Heteroplasmy — tissue testing implications
    DefinitionHeteroplasmy is the presence of more than one mitochondrial DNA (mtDNA) variant (a mixture of mutant and wild-type mtDNA) within a tissue or individual; levels can vary by tissue and affect detectability.
    Testing implicationTissue selection (e.g., urine, muscle) is important because blood testing can be negative despite pathogenic mtDNA in other tissues; document tissue source and rationale.
    Clinical noteUrine heteroplasmy analysis may be more informative for certain mutations (e.g., m.3243A>G) and mtDNA deletion/duplication and copy number testing should be considered when appropriate.
    Heteroplasmy (duplicate entry)
    DefinitionHeteroplasmy: mixture of more than one mtDNA type within a cell or individual; level varies by tissue and affects detection and interpretation.
    Laboratory impactLow-level heteroplasmy may be missed in blood; consider alternative tissues and sensitive NGS methods for detection.
    Clinical implicationDocument prior negative blood testing if alternate tissue is used for mtDNA analysis and rationale for tissue selection.
    Chromosomal microarray (CMA)
    DefinitionChromosomal microarray (CMA) is array-based testing for copy number variants and is recommended as first-line diagnostic testing for developmental delay/intellectual disability (DD/ID), autism spectrum disorder (ASD), and multiple congenital anomalies.
    IndicationsCMA is indicated for GDD/ID, ASD, multiple congenital anomalies, and short stature when clinically appropriate; not indicated for isolated speech/language delay.
    Guideline supportRecommendations supported by AAP and ACMG practice resources as standard first-tier testing in these indications.
    Autism spectrum disorder (DSM-5)
    DefinitionAutism spectrum disorder (ASD) is defined per DSM-5 as persistent deficits in social communication and social interaction across contexts, including deficits in social-emotional reciprocity and nonverbal communicative behaviors.
    Clinical featuresASD manifestations include deficits in social‑emotional reciprocity, nonverbal communicative behaviors, and difficulties developing/maintaining relationships.
    Context for testingASD is a listed indication for chromosomal microarray and may prompt additional genetic testing per clinical guidance.
    Close relatives
    DefinitionClose relatives include first-, second-, and third-degree blood relatives: first-degree = parents, siblings, children; second-degree = grandparents, aunts/uncles, nieces/nephews, half-siblings; third-degree = great-grandparents, great-aunts/uncles, first cousins.
    Use in criteriaFamily history of an affected first-degree relative can qualify for genetic testing in several disorder-specific criteria (e.g., NF1, some connective tissue disorders, BWS).
    Developmental delay (DD)
    DefinitionDevelopmental delay (DD) refers to slow-to-meet or not reaching developmental milestones in one or more areas relative to age expectations.
    DistinctionGlobal developmental delay (GDD) applies to children under age 5 with delays in ≥2 domains; otherwise use DD/ID terminology for older children.
    Testing implicationDD is an indication to consider CMA and further genetic evaluation per policy criteria.
    Exome Sequencing (ES)
    DefinitionExome Sequencing (ES) sequences all protein-coding regions of genes (the exome).
    RoleES is indicated for congenital anomalies, unexplained DD/ID, or when guideline-recommended; reanalysis after >18 months may be considered.
    Rapid ESRapid ES is supported for acutely ill infants when results will impact immediate management.
    Genome Sequencing (GS)
    DefinitionGenome Sequencing (GS) sequences the complete DNA including coding and non-coding regions.
    RoleGS may be used when ES is nondiagnostic or when broader coverage is indicated; rapid GS is supported for acutely ill infants if it informs urgent management.
    Comparison to ESWGS can identify variants not captured by ES; reanalysis and platform considerations may affect reuse of previous data.
    Global Developmental Delay (GDD) — duplicate definition
    DefinitionGlobal Developmental Delay (GDD): child under age 5 who is slow to meet milestones in at least two developmental domains.
    Diagnostic ageGDD designation is reserved for children under age 5; beyond that age, consider ID evaluation.
    Implication for rapid testingGDD under age 5 is an eligible indication for rapid ES/GS when clinically appropriate.
    Intellectual Disability (ID)
    DefinitionIntellectual Disability (ID): deficits in intellectual and adaptive functioning with onset during developmental period per DSM‑V.
    Testing implicationID is an indication for genetic evaluation including CMA and consideration of ES/GS per guidelines.
    AssessmentDiagnosis requires clinical assessment and standardized testing to document intellectual and adaptive deficits.
    Global developmental delay — updated applicability
    UpdateDefinition of global developmental delay was clarified to specify applicability under age 5 for rapid genomic testing criteria.
    Policy impactThis definition guides eligibility for rapid ES/GS and related reanalysis provisions in the policy.
    ReferenceSee rapid sequencing and reanalysis sections for operational details on timing and indications.
    Type A / Type B aortic dissection
    Definition changeType A and Type B aortic dissection definitions were moved under a shared definition within the policy for clarity.
    Type AType A dissections occur at the ascending aorta near the heart.
    Type BType B dissections occur in the descending aorta and may extend into the abdomen.

    Policy Updates and Material Changes

    04/24revised

    Multiple disorder-specific criteria were revised including NF1 (enumerated diagnostic features added), Noonan/RASopathy panels (changed 'any' to 'at least one' and SPRED1 added; minimum gene lists removed), PIK3CA criteria (changed to require at least one feature and removed del/dup), and other granular wording/age edits across sections.

    added

    Criteria for mitochondrial genome sequencing, deletion/duplication, and nuclear gene panels were consolidated into this multisystem policy from a previously separate policy.

    revised

    NF2 testing indications were operationalized with added adult and pediatric clinical criteria and older code references removed/replaced.

    revised

    Policy consolidated additional criteria from prior connective tissue and rapid/standard exome/genome sequencing policies; investigational language was updated to 'current evidence does not support…' and definitions (e.g., global developmental delay age) were clarified.

    Policy language was updated to replace prior 'investigational' terminology in some sections with the phrasing 'current evidence does not support…', clarifying that certain tests (for example some ASD/ID panels and other listed analyses) lack sufficient evidence for broad use and therefore require indication‑specific justification.

    Older numeric code references and some example entries were removed or revised in the update; revisions also operationalized NF2 testing indications and added pediatric criteria. Providers must use the updated policy reference table and follow revised clinical criteria when requesting prior authorization or submitting claims.