ModifiedArizona Complete HealthPolicy N/A

Genetic and molecular testing for neurological conditions

Governs use and coding implications of genetic and molecular tests (multigene panels, sequencing, deletion/duplication, repeat analyses) for evaluation of neurological conditions; includes examples, condition-specific criteria, and coding guidance.

Policy Summary

PayerArizona Complete Health

PolicyGenetic and molecular testing for neurological conditions

Policy CodePolicy N/A

Change TypeMultiple editorial updates and several material revisions (criteria consolidations, age restrictions, APOE clarification)

Effective DateN/A

Next Review DateN/A

Key ActionDocument and confirm that required clinical criteria and prior testing are present when requesting genetic or molecular testing; follow consolidated policy for known familial variant authorizations.

SourceLink

POLICY UPDATE CHANGES

Updated titles and wording across many panels (e.g., changed 'Neuromuscular NGS Panel' to 'Comprehensive Neuromuscular Disorders Panel'; renamed multiple panels and standardized language).

Replaced the phrase 'coverage criteria' with 'criteria' throughout the document.

Moved Variant Analysis for Epilepsy, Neurodegenerative, and Neuromuscular disorders criteria into the 'Genetic Testing: General Approach to Genetic and Molecular Testing' policy to consolidate criteria for known familial variant tests.

Added age restriction for HTT (Huntington disease) repeat analysis (must be 18 or older).

Removed age restriction (18+) for Amyotrophic Lateral Sclerosis (ALS) multigene panel to allow childhood-onset testing.

Reworded APOE Variant Analysis language to evaluate suitability for monoclonal antibody treatment and added criterion for diagnosis of Alzheimer's disease; added Kisluna as example therapy guided by testing.

numerouscondition-specific criteria

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presentexample CPT/ICD references

APOE linkedAPOE guidance

>=18HTT age restriction

age removedALS age rule

~25epilepsy panel min genes

Coverage Criteria for Genetic and Molecular Testing — Neurology

I. PMP22 sequencing and/or deletion/duplication analysis or multigene panel analysis to establish a genetic diagnosis of an inherited peripheral neuropathy (including Charcot-Marie-Tooth disease [CMT] and Hereditary Neuropathy with Liability to Pressure Palsies [HNPP]) is considered medically necessary when ALL of the following are met:

A. The member/enrollee displays one or more of the following clinical features consistent with an inherited peripheral neuropathy:

1. Distal muscle weakness and atrophy (typically symmetric, progressive), OR

2. Pes cavus (high-arched feet) or other foot deformity, OR

3. Weak ankle dorsiflexion or foot drop, OR

4. Depressed or absent tendon reflexes in affected limbs, OR

5. Recurrent acute focal sensory and motor neuropathies mainly at entrapment sites (suggestive of HNPP), OR

6. Painless nerve palsy after minor trauma or compression, OR

7. Evidence on physical examination of prior focal nerve palsy such as focal weakness, atrophy, or sensory loss, OR

8. Complete or near-complete spontaneous recovery from neuropathies (commonly seen in HNPP).

B. Electrodiagnostic testing (e.g., nerve conduction studies and EMG) and/or clinical evaluation support a peripheral neuropathy phenotype (e.g., predominantly demyelinating or axonal features) and other acquired causes have been reasonably excluded (e.g., diabetes, toxic/metabolic, inflammatory, infectious, vitamin deficiencies, compressive etiologies where not typical).

C. One of the following testing-intent conditions applies:

1. The member/enrollee's phenotype is not consistent with a single-gene test being clearly appropriate (i.e., multiple genes could explain the presentation), making a multigene panel the preferred initial test, OR

2. The member/enrollee underwent targeted or single-gene testing (e.g., PMP22 dosage testing) and results were non-diagnostic, OR

3. There is clinical suspicion for PMP22 copy-number alteration (e.g., recurrent entrapment neuropathies, transient nerve palsies, family history consistent with HNPP) in which case PMP22 deletion testing (deletion/duplication analysis) is appropriate.

II. The diagnosis of HNPP is established in a proband with suggestive clinical findings by identification of either:

A. The recurrent 1.5-megabase (Mb) deletion involving PMP22 (most common, ~80% of cases), OR

B. A pathogenic (or likely pathogenic) PMP22 sequence variant or other pathogenic variant affecting PMP22 (approximately 20% of cases).

III. Current evidence does not support PMP22 sequencing and/or deletion/duplication analysis or multigene panel analysis to establish a genetic diagnosis of an inherited peripheral neuropathy for other indications not described above.

title':'Charcot-Marie-Tooth (CMT) and HNPP Criteria

type':'criteria_group'}],

Coding and Billing References

Example CPT codes (not exhaustive)CPT

81161	Example comprehensive testing code referenced
81404	NGS or panel testing code referenced

Disease-specific example codesCPT

81302	MECP2 sequencing example
81271	HTT repeat analysis example

Panel and unlisted codesCPT

81406	Multigene panel code referenced for myotonia/periodic paralysis
81479	Unlisted molecular pathology code used in panels

Referenced CPT/ICD-10 codes for genetic tests and mapped conditionsmixed

81406	Targeted gene sequencing/analysis codes referenced for panels and single gene testing
81407	Targeted gene panel/sequence analysis code referenced
81479	Unlisted molecular pathology procedure code referenced
81400	Molecular cytogenetics/other panel codes referenced
G70.2	Myasthenia gravis ICD-10 code referenced as phenotype mapping
G71.12	Myotonia congenital ICD-10 code referenced
E87.6	Hypokalemia ICD-10 referenced in periodic paralysis context

Genetic test typesmixed

Multiple single-gene tests, repeat analyses, deletion/duplication analyses, and multigene panels referenced; specific coding not listed in this segment.

DMD testing methodsmixed

MLPA or comparative genomic hybridization array recommended first for dystrophin deletions/duplications

Multigene panel requirementsmixed

Multigene panels with copy number analysis for epilepsy and ALS gene panels; epilepsy panels should include minimum of 25 genes

Panels renamed/retitledmixed

No codes listed

Policy reference/test name updatesmixed

Example test names in Policy Reference Table were updated across multiple panels (e.g., Epilepsy Multigene Panel, DMD, APOE).

Referenced literature (no billing codes)mixed

Numerous guideline and GeneReviews references cited (no explicit billing/CPT/HCPCS/ICD codes present in these chunks).

Comprehensiveness

Scope of listed codes/testsCPT codes and tests referenced are examples and not comprehensive; inclusion or exclusion does not guarantee coverage.

Informational use onlyCodes and CPT descriptions are included for informational purposes only; providers should reference current coding guidance before claim submission.

Concert PlatformAdditional registered tests are available on the Concert Platform (see policy note).

CK elevation thresholds for DMD/BMD

Provider Actions, Documentation, and Recommended Testing Approaches

Note

Overview — tests for neurological conditions

This policy addresses the use of tests for evaluation of neurological conditions. It provides guidance on medical necessity documentation, required prior testing, clinical criteria for predictive testing, requirements for APOE testing prior to anti-amyloid monoclonal antibody therapy, the recommended diagnostic testing sequence for Duchenne muscular dystrophy (DMD), and the purpose and limitations of the policy.

Documentation Required

Medical necessity documentation and prior testing

It is the policy of health plans affiliated with Centene Corporation® that the specific genetic testing noted below is medically necessary when meeting the related criteria. Providers must document medical necessity in the patient record, including clinical findings, relevant family history, and prior testing performed. Prior testing results that would typically be required or reviewed include prior genetic test reports for the same condition (if available), relevant biochemical or imaging studies (e.g., creatine kinase for suspected muscular dystrophy, brain imaging for neurodegenerative disease), and any prior electrophysiologic testing when relevant (e.g., EMG for myotonic disorders). For predictive testing, documentation must include evidence of pre-test genetic counseling and informed consent, and for minors, predictive testing is only considered when consistent with policy age restrictions and professional guidance.

Definitions, Test Scope, and Notes

CPT codes referenced for informational purposes only

Example CPT codes81161, 81404 are shown as example comprehensive testing/panel codes (informational only).

Panel/unlisted codes81406 and 81479 are referenced as panel and unlisted molecular pathology examples.

Mapping to diagnosesDocument also references ICD-10/phenotype codes (e.g., G70.2, G71.12) associated with genetic test mappings.

Not exhaustiveListed CPT/ICD codes are examples and not intended to be all-inclusive.

Location for additional registered tests

Concert Platform locationThe policy notes that additional registered tests can be found on the Concert Platform.

Policy Summary

PayerArizona Complete Health

PolicyGenetic and molecular testing for neurological conditions

Policy CodePolicy N/A

Change TypeMultiple editorial updates and several material revisions (criteria consolidations, age restrictions, APOE clarification)

Effective DateN/A

Next Review DateN/A

SourceLink

On This Page

DMD CK thresholdElevated serum creatine kinase concentration typically more than 10 times the normal levels for DMD.

BMD CK thresholdElevated serum creatine kinase concentration typically more than 5 times the normal levels for BMD.

Clinical contextCK thresholds are part of the clinical criteria used to determine medical necessity for diagnostic DMD sequencing/deletion-duplication analysis.

Attacks with documented hypokalemia

Attack frequencyTwo or more attacks of muscle weakness with documented serum potassium less than 3.5 mEq/L.

Alternate family-history criterionOne attack in proband plus one attack in a close relative with documented serum potassium < 3.5 mEq/L counts toward diagnosis.

Additional supportive featuresThree or more specific clinical/laboratory features (e.g., onset in first/second decade, prolonged attacks, triggers, improvement with potassium, family history, positive long exercise test) may establish diagnosis when attacks are fewer.

Minimum genes for epilepsy panel

Minimum gene countEpilepsy multigene panels should include a minimum of 25 genes.

Copy number analysisPanel should include copy number analysis (CNV/CNV detection) as part of testing.

First-tier recommendationMulti-gene comprehensive testing (exome/genome or multigene panel) recommended as first-tier for unexplained epilepsy regardless of age.

Repeat count thresholds (DM1/DM2)

DM1 repeat thresholdPatients with more than 50 CTG repeats in the DMPK gene are considered to have DM1.

DM2 repeat thresholdPatients with more than 75 CCTG repeats in CNBP (ZNF9) are considered to have DM2; 28–75 repeats represent a gray zone.

Testing recommendationMolecular genetic testing is first-line for suspected DM1/DM2; muscle biopsy generally not recommended when testing available.

Document clinical findings and family history in the medical record.
Attach prior relevant genetic test reports and supporting laboratory/imaging results.
Provide evidence of pre-test counseling and informed consent for predictive testing.

Documentation Required

Clinical criteria and predictive testing requirements

Clinical criteria and requirements for predictive testing must be met as described in the specific test criteria sections. Predictive (presymptomatic) testing should be performed only when: the individual is asymptomatic, a pathogenic or likely pathogenic familial variant has been identified in a relative (when applicable), and thorough pre- and post-test genetic counseling is provided. Age restrictions specified in individual sections must be followed (e.g., HTT predictive testing limited to individuals 18 years or older). Predictive testing without appropriate counseling or documentation of indication may be considered not medically necessary.

Predictive testing requires documented pre- and post-test genetic counseling.
Follow age restrictions noted in specific test criteria (e.g., HTT ≥ 18 years).
Testing for a familial variant should reference an identified pathogenic or likely pathogenic variant in a relative when applicable.

Prior Authorization

APOE testing before anti-amyloid mAb therapy

APOE variant analysis (APOE e4 testing) should be completed prior to initiation of anti-amyloid monoclonal antibody therapy (for example, Leqembi or Kisluna) when the member is being evaluated for suitability of such treatment. This testing is recommended because APOE e4 carrier status (particularly homozygosity) is associated with an increased risk of amyloid-related imaging abnormalities (ARIA), including symptomatic and serious events. Documentation should include the Alzheimer disease diagnosis or clinical evaluation supporting consideration of monoclonal antibody therapy and the APOE test result prior to treatment initiation, as required by the FDA labeling.

Indication: Member being evaluated for suitability of anti-amyloid monoclonal antibody therapy.
Require documentation of Alzheimer's disease diagnosis or clinical assessment supporting treatment consideration.
Include APOE test result in the medical record prior to therapy start.

Note

DMD diagnostic testing sequence

For suspected Duchenne muscular dystrophy (DMD), the recommended diagnostic testing sequence is: 1) deletion/duplication analysis of the DMD (dystrophin) gene as the first-line confirmatory test (methods such as MLPA or comparative genomic hybridization array are preferred because they detect single- and multi-exon deletions/duplications and help define reading-frame consequences); 2) if deletion/duplication testing is negative and clinical suspicion remains, proceed to sequencing of the DMD gene (next-generation sequencing) to detect point mutations, small insertions/deletions, or other sequence variants (~25–30% of DMD mutations); 3) if genetic testing is inconclusive but clinical diagnosis persists, obtain muscle biopsy with dystrophin protein testing by immunohistochemistry or western blot. Documentation should include clinical signs (e.g., proximal muscle weakness), creatine kinase results when available, and the sequence of testing performed.

First-line: DMD deletion/duplication testing (MLPA or comparative genomic hybridization array).
Second-line: DMD sequencing (next-generation sequencing) if deletion/duplication testing is negative.
Third-line: Muscle biopsy with dystrophin protein testing if genetic testing is non-diagnostic.

Note

Policy purpose and limitations

Important Reminder: This clinical policy is intended to guide determinations of medical necessity and to assist in coverage decisions. It was developed by qualified health care professionals based on available evidence, guidelines, and expert input. It does not constitute medical advice, a guarantee of payment, or a substitute for professional judgment. Coverage decisions remain subject to the terms of the member's plan, applicable laws and regulations, and Health Plan administrative policies. For Medicaid members, state Medicaid provisions take precedence when there is a conflict. Providers are expected to document clinical rationale thoroughly and to follow applicable regulatory and plan-level requirements.

This policy guides medical necessity determinations but is not a guarantee of coverage.
State Medicaid provisions supersede policy if conflicts exist.
Providers retain responsibility for clinical care and documentation.

Use for updated test listsProviders should consult Concert for current registered tests and test names referenced by the Health Plan.

Definition of medical necessity

DefinitionMedically necessary genetic testing meets the specific clinical criteria outlined in this policy for the indicated condition.

Documentation requirementProviders must document clinical signs/symptoms and prior targeted testing where applicable to support medical necessity.

Predictive testing counseling requirement

Counseling requirementPredictive testing should only be performed in the setting and context of thorough pre- and post-test counseling.

HTT-specificPredictive testing for Huntington disease requires age ≥18 and counseling; close-relative/family-history conditions apply.

Familial testing guidanceAsymptomatic/familial predictive testing criteria specify relationship requirements (e.g., sibling, obligate carrier) and counseling.

Panel vs single-gene testing guidance

When to use panelsMultigene panels are recommended when phenotype is not clearly indicative of a single gene or when genetic heterogeneity exists.

When single-gene is appropriateSingle-gene testing may be appropriate for characteristic phenotypes with high clinical suspicion (e.g., clear DMD features, classic myotonic dystrophy).

Panel composition notePanels should include copy number analysis for conditions where CNVs are relevant (eg epilepsy, neuromuscular panels).

SMN1/SMN2 testing details and newborn screening

SMN1/SMN2 methodsSMN1 sequencing and/or deletion/duplication analysis for SMA; SMN2 copy-number analysis via gene-targeted deletion/duplication testing can be performed for clinical correlation if diagnosis confirmed.

Newborn screeningNewborn screening for SMA primarily uses realtime PCR to detect the common SMN1 deletion; positive NBS should have confirmatory molecular testing.

Panel inclusionSymptomatic individuals may have single-gene SMN1 testing or a multigene panel that includes SMN1 and SMN2 and other relevant genes.

MECP2 disorder features

Core featuresRett syndrome (MECP2 disorder) commonly presents with regression (ages 1–4), loss of purposeful hand skills, loss of spoken language, gait abnormalities, and stereotypic hand movements.

Exclusionary findingsSevere brain injury, neurometabolic disease, or grossly abnormal early psychomotor development are exclusionary for MECP2 disorder testing.

APOE e4 testing rationale

Rationale for testingAPOE genotype (e4) testing is used to stratify ARIA risk and should be completed prior to anti-amyloid monoclonal antibody therapy (per FDA labels).

Treatment examplesAPOE variant analysis language updated to assess suitability for monoclonal antibody therapies such as Leqembi and Kisluna.

Indication tied to diagnosisAPOE variant analysis is indicated when the member has Alzheimer’s disease and is being evaluated for suitability of monoclonal antibody treatment.

DMD diagnostic approach

Initial DMD testBegin with deletion/duplication testing (eg MLPA or comparative genomic hybridization array) because ~70% of DMD cases are exon deletions/duplications.

Reflex to sequencingIf deletion/duplication testing is negative, proceed to sequencing to detect point mutations/small indels (~25–30% of DMD mutations).

If inconclusiveIf genetic testing does not confirm DMD, consider muscle biopsy for dystrophin protein testing by IHC or western blot.

Autosomal dominant definition

DefinitionAutosomal dominant inheritance is characterized by affected individuals in multiple generations and transmission from an affected parent to offspring.

ImplicationAutosomal dominant patterns inform testing decisions for disorders such as Huntington disease and certain early-onset Alzheimer genes.

Other definitions (age, neonate, close relative)

ChildhoodChildhood is defined as development until the 18th birthday.

NeonateA neonate is a baby who is four weeks old or younger.

Close relativesClose relatives include first-, second-, and third-degree blood relatives (definitions provided).

Repeat expansion thresholds (DM1/DM2)

DM1 thresholdDM1: >50 CTG repeats in the DMPK gene indicates DM1.

DM2 thresholdDM2: >75 CCTG repeats in CNBP (ZNF9) indicates DM2; 28–75 repeats are a gray zone requiring further evaluation.

Testing approachRepeat sizing in tissues other than blood and/or segregation studies may be valuable for clarifying pathogenicity in gray-zone cases.

APOE Variant Analysis (examples and purpose)

Purpose examplesAPOE variant analysis examples include Leqembi and Kisluna; used to assess suitability for monoclonal antibody therapy by stratifying ARIA risk.

APOE e4 relevanceAPOE e4 homozygotes have increased incidence of ARIA compared to heterozygotes and noncarriers (per FDA drug labels).

DMD Diagnostic Sequencing (naming/usage note)

Naming/usage noteCriteria name 'Diagnostic DMD Sequencing and/or Deletion/Duplication Analysis' distinguishes prenatal vs postnatal testing and clarifies testing sequence.

Preferred methodsDeletion/duplication testing by MLPA or CGH array is preferred first-line; sequencing used if negative.

Important Reminder / Legal and administrative notices

Policy purposeThis clinical policy is guidance to assist coverage decisions and administration of benefits; it does not guarantee payment or constitute medical advice.

State/Medicaid precedenceFor Medicaid members, state Medicaid provisions take precedence over this clinical policy if conflicts exist.

Medicare guidanceFor Medicare members, review applicable NCDs and LCDs to ensure consistency before applying this policy.