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CurrentWellCarePolicy N/A

Genetic Testing: Epilepsy, Neurodegenerative, and Neuromuscular Disorders — Coverage Criteria

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Criteria and coding guidance for genetic testing used to diagnose hereditary epilepsy, neurodegenerative, and neuromuscular diseases when conventional diagnostics are inconclusive; intended for providers ordering or billing these tests under WellCare.

Policy Summary

PayerWellCare

PolicyGenetic Testing: Epilepsy, Neurodegenerative, and Neuromuscular Disorders — Coverage Criteria

Policy CodePolicy N/A

Change TypeNo material clinical or coverage changes

Effective DateN/A

Next Review DateN/A

Key ActionVerify prior authorization requirements and submit the mapped procedure codes with matching diagnosis documentation when requesting listed genetic tests.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

multipleconditions described

manyprocedure codes referenced

~20+distinct panels/genes referenced

>=25epilepsy panel min genes

03/23internal policy timestamp

Coverage Criteria for Genetic & Molecular Testing

Diagnostic genetic testing — general — Covered when ALL of the following are met

Diagnostic genetic testing — general — Covered when ALL of the following are met:

ALL of the following

The test is ordered by an appropriate specialist (e.g., neurologist, geneticist) and results will impact clinical management.
Clinical features or family history are consistent with the suspected disorder as described in disorder-specific criteria below.
Alternative, non-genetic causes have been considered and where appropriate ruled out; prior noninvasive testing was non-diagnostic or not indicated.
Results will be interpreted in the context of pre- and post-test genetic counseling when predictive or familial testing is performed.

Policy Summary

PayerWellCare

PolicyGenetic Testing: Epilepsy, Neurodegenerative, and Neuromuscular Disorders — Coverage Criteria

Policy CodePolicy N/A

Change TypeNo material clinical or coverage changes

Effective DateN/A

Next Review DateN/A

Key ActionVerify prior authorization requirements and submit the mapped procedure codes with matching diagnosis documentation when requesting listed genetic tests.

SourceLink

On This Page

Known Familial Variant Analysis — Targeted mutation analysis for a known familial variant is covered when ALL of the following are met:

ALL of the following

The member/enrollee has a close relative with a known pathogenic or likely pathogenic variant causing the condition.
The specific familial variant and its clinical significance are documented in the medical record or laboratory report of the affected relative.
Testing is limited to the known familial variant(s) and not broader sequencing unless clinically justified and documented.

Comprehensive Ataxia Panel — Covered when ALL of the following are met:

ALL of the following

The member/enrollee displays one or more clinical features of spinocerebellar ataxia (e.g., poorly coordinated gait, dysarthria, limb ataxia).
Non‑genetic causes of ataxia have been reasonably excluded (e.g., alcoholism, vitamin deficiency, MS, vascular disease, neoplasm, paraneoplastic syndromes).
Either there is no strong suspicion for a single‑gene cause for which targeted testing would be more appropriate, or prior single‑gene testing was non‑diagnostic.

Comprehensive Neuromuscular Disorders Panel — Covered when ALL of the following are met:

ALL of the following

The member/enrollee displays clinical features of a neuromuscular disorder (e.g., progressive weakness, elevated CK, EMG evidence of myopathy or neuropathy).
Either no specific neuromuscular disorder is highly suspected for which single‑gene testing (e.g., SMN1, DMD, PMP22) would be more appropriate, OR prior single‑gene testing was performed and did not definitively lead to a diagnosis.

SMN1 Sequencing and/or Deletion/Duplication Analysis — Covered when ANY of the following are met:

ANY of the following

The member/enrollee has a positive newborn screen for spinal muscular atrophy (SMA).
The member/enrollee has clinical features consistent with SMA such as history of motor difficulties with loss of milestones, proximal greater than distal weakness, hypotonia, decreased/absent deep tendon reflexes, tongue fasciculations, or evidence of motor unit disease on EMG.
Genetic testing is being performed for familial cascade testing when a pathogenic SMN1 variant has been identified in a close relative (targeted familial testing preferred).

Epilepsy Multigene Panel — Covered when ALL of the following are met:

ALL of the following

The member/enrollee has a history of unexplained epilepsy (seizures not attributable to an acquired etiology such as trauma, infection, structural brain abnormality, or stroke).
The results of genetic testing will influence clinical management (e.g., anti‑seizure medication selection, prognosis, family planning) or aid diagnosis when standard workup has been inconclusive.

SMN2 Deletion/Duplication Analysis — Covered when ALL of the following are met:

ALL of the following

The member/enrollee has a confirmed diagnosis of spinal muscular atrophy (SMA).
SMN2 copy number determination is performed to inform prognosis and potential treatment decisions when clinically indicated.

PSEN1/PSEN2/APP Sequencing or Panel — Covered when ALL of the following are met:

ALL of the following

Testing is to establish a diagnosis or determine future risk for early‑onset Alzheimer disease (EOAD) due to PSEN1, PSEN2, or APP variants.
For asymptomatic individuals: age ≥ 18 and a close relative has a known EOAD‑causing mutation in PSEN1, PSEN2, or APP, OR there is an apparent autosomal dominant family history of dementia with one or more early‑onset cases.
For symptomatic individuals: dementia onset ≤ 65 years, with either a close relative diagnosed with dementia or unknown family history (e.g., adoption); or dementia at any age with an autosomal dominant family history and at least one close relative with dementia < 65 years.

APOE, TREM2 and Other Variant Analysis — Testing of APOE, TREM2, and other non-PSEN/APP genes for Alzheimer disease is:

APOE, TREM2 and Other Variant Analysis — Testing of APOE, TREM2, and other non‑PSEN/APP genes for Alzheimer disease is:

ALL of the following

Considered investigational to establish diagnosis or determine future risk for Alzheimer disease (including APOE and TREM2).
Routine APOE genotyping for Alzheimer disease risk prediction is not recommended and typically not covered; predictive testing should only be done with thorough pre‑ and post‑test genetic counseling when clinically justified.

Familial Amyotrophic Lateral Sclerosis (FALS) Multigene Panel — Covered when ALL of the following are met:

ALL of the following

The member/enrollee is 18 years of age or older.
The member/enrollee displays clinical features of ALS including evidence of lower motor neuron degeneration, evidence of upper motor neuron degeneration, progressive spread of symptoms, and no alternative disease processes explaining the findings.
The multigene panel includes at minimum the key ALS genes (e.g., C9orf72, SOD1, FUS, TARDBP).

DMD Sequencing and/or Deletion/Duplication Analysis — Covered when ANY of the following groups of criteria are met:

ANY of the following

Male with clinical features
- Progressive symmetric proximal > distal weakness with or without calf pseudohypertrophy, symptoms presenting in childhood (often before age 5), wheelchair dependence by early teens, and markedly elevated serum creatine kinase (typically >10x normal).
Female or asymptomatic at‑risk individuals
- Asymptomatic individuals who are biological siblings of an affected person, obligate carriers, or females with a first‑ or second‑degree relative with DMD/BMD; testing is for carrier or cascade diagnostic purposes.
Becker muscular dystrophy (BMD) phenotype
- Elevated CK (typically >5x normal) with milder/later onset weakness, activity‑induced cramping, flexion contractures, or wheelchair dependence later in life; testing to confirm diagnosis.

Facioscapulohumeral Muscular Dystrophy (FSHD) Testing — Covered when ALL of the following are met:

ALL of the following

The member/enrollee displays clinical features consistent with FSHD such as asymmetric weakness predominantly affecting facial, scapular stabilizer, or foot dorsiflexor muscles, progression after pregnancy, or prior diagnosis with inflammatory myopathy refractory to immunosuppression.
Testing includes FSHD1 deletion/haplotype analysis and as indicated SMCHD1 and DNMT3B sequencing or deletion/duplication analysis to establish or confirm diagnosis.

Friedreich Ataxia (FXN) Testing — Covered when ANY of the following are met:

ANY of the following

Asymptomatic individuals who have a biological sibling diagnosed with Friedreich ataxia (cascade testing).
Symptomatic individuals
- The member/enrollee has cerebellar ataxia AND non‑genetic causes for ataxia have been ruled out (e.g., alcoholism, vitamin deficiencies, MS, vascular disease, tumors).

PMP22 Sequencing/Deletion/Duplication or Charcot‑Marie‑Tooth (CMT) Panel — Covered when ALL of the following are met:

ALL of the following

The member/enrollee displays one or more clinical features of an inherited peripheral neuropathy such as distal muscle weakness/atrophy, sensory loss, pes cavus, weak ankle dorsiflexion, or depressed tendon reflexes.
The member/enrollee does not already have a clinical genetic diagnosis of CMT or HNPP; testing includes PMP22 and a panel that at minimum contains PMP22, GDAP1, GJB1, HINT1, MFN2, MPZ, SH3TC2, and SORD when a panel is used.

Limb‑Girdle Muscular Dystrophy Multigene Panel — Covered when ALL of the following are met:

ALL of the following

The member/enrollee displays slowly progressive symmetrical weakness with limb‑girdle pattern affecting proximal arms and legs, scapuloperoneal weakness, distal weakness, or elevated serum CK.
Alternatively, testing is appropriate in asymptomatic individuals with a close relative diagnosed with limb‑girdle muscular dystrophy when the relative's genetic status is unavailable.

Myotonic Dystrophy (DM1 and DM2) Testing — Medically necessary when ANY of the following are met:

ANY of the following

The member/enrollee has clinical features consistent with myotonic dystrophy such as myotonia, progressive muscle weakness, early cataracts, cardiac conduction defects, or family history consistent with autosomal dominant inheritance.
Predictive or carrier testing for asymptomatic individuals is performed with documented pre‑ and post‑test genetic counseling and a known familial pathogenic repeat expansion in DMPK (DM1) or CNBP (DM2).

Disorder‑specific Multigene Panels — Coverage note:

Disorder‑specific and Other Multigene Panels — Coverage note:

ALL of the following

Disorder‑specific multigene panels are considered medically necessary when clinical presentation and prior testing meet the specific criteria outlined above for the disorder targeted by the panel.
A multigene panel should include at minimum the genes listed in the disorder‑specific criterion where specified; panels that do not include relevant genes may be insufficient and require justification.
Each listed test is considered investigational for all other indications not explicitly described in the covered criteria; inclusion of CPT codes does not guarantee coverage — local coding and coverage rules apply.

Coverage caveats and investigational stance — Consolidated statements:

ALL of the following

Each listed test is considered investigational for indications other than those explicitly described in the covered criteria.
Routine APOE genotyping for Alzheimer disease risk prediction is not recommended and thus typically not covered; predictive APOE testing should only be performed with thorough pre‑ and post‑test counseling.
Predictive genetic testing for adult‑onset conditions should be accompanied by appropriate genetic counseling and informed consent.

Covered Indications and Condition-Specific Criteria

inv-132: Confirming a diagnosis in symptomatic patients with suspected hereditary epilepsy, neurodegenerative, or neuromuscular disease when standard diagnostic methods are inconclusive.

Covered when testing is consistent with recommended diagnostic pathways for spinal muscular atrophy:

SMA testing indications: Newborn screening positive for SMN1 deletion requires confirmatory molecular testing; symptomatic individuals with clinical features of SMA may have single-gene SMN1 testing or multigene panels including SMN1/SMN2; SMN2 copy number analysis can provide additional clinical correlation if diagnosis is confirmed.

Codes: 81329, 81336, 81401, 81405

inv-133: Limb-girdle muscular dystrophy, Charcot-Marie-Tooth, myotonic dystrophy, hereditary dystonia, Parkinson disease, hereditary spastic paraplegia, congenital myasthenic syndromes, myotonia congenita, hypokalemic periodic paralysis and other neuromuscular/neurodegenerative disorders.

Covered when phenotype and clinical context align with the listed disorders and panels:

Disorders commonly covered: Limb-girdle muscular dystrophy, Charcot–Marie–Tooth (CMT), myotonic dystrophy, hereditary dystonia, Parkinson disease, hereditary spastic paraplegia, congenital myasthenic syndromes, myotonia congenita, hypokalemic periodic paralysis, and other neuromuscular/neurodegenerative disorders when clinical criteria specified per condition are met.

See disorder-specific sections for required features and minimum gene lists (e.g., PMP22 for CMT; SPAST/ATL1/KIF1A/CYP7B1/SPG7/SPG11 for HSP)

inv-134: Diagnosis or confirmation of specified genetic neurological disorders (examples include SMA, DMD/BMD, familial ALS, Friedreich's ataxia, FSHD, early-onset Alzheimer disease, Huntington disease, inherited peripheral neuropathies, epilepsy of unknown cause, ataxia).

Diagnosis or confirmation of the following genetic neurological disorders is covered when the specific clinical and/or family-history criteria listed for each test are met:

Examples of covered disorders: Spinal muscular atrophy (SMN1/SMN2), Duchenne/Becker muscular dystrophy (DMD/BMD), familial amyotrophic lateral sclerosis (FALS), Friedreich's ataxia (FXN), facioscapulohumeral muscular dystrophy (FSHD), early-onset Alzheimer disease (PSEN1/PSEN2/APP), Huntington disease (HTT), inherited peripheral neuropathies (including PMP22), epilepsy of unknown cause, and ataxia.

Each disorder has condition-specific entry criteria and minimum panel/gene content where specified

Procedure and Diagnosis Codes

Known Familial Variant Analysis example CPT CodesCPT

81403	Targeted mutation analysis
81174	Targeted analysis (listed)

Comprehensive Neuromuscular Disorders Panel CPT CodesCPT

81186	Referenced in comprehensive neuromuscular panels
81190	Referenced in comprehensive neuromuscular panels
81289	Referenced in comprehensive neuromuscular panels
81326	Referenced in comprehensive neuromuscular panels
81337	Referenced in comprehensive neuromuscular panels

Epilepsy Multigene Panel CPT CodesCPT

81185	Epilepsy multigene panel / childhood/infantile epilepsy panels
81189	Epilepsy multigene panel
81302	Epilepsy multigene panel
81406	Epilepsy multigene panel
81419	Epilepsy multigene panel
81479	Unlisted molecular pathology; referenced with panels

Repeat expansion testing CPT Codes (FXN, HTT)CPT

81284	FXN Repeat Analysis
81285	FXN Repeat Analysis
81286	FXN Sequencing Analysis
81271	HTT Repeat Analysis
81274	HTT Repeat Analysis

DMD testing CPT CodesCPT

81161	DMD Deletion/Duplication Analysis
81408	DMD Sequencing Analysis

Familial ALS (FALS) Multigene Panel Codesmixed

81179	Familial ALS / multigene components referenced
81403	ALS panel component
81404	ALS panel component
81405	ALS panel component
81406	ALS panel component
81407	ALS panel component
S3800	ALS related test (proprietary/stacked)

FSHD and related testing CPT CodesCPT

81404	FSHD1 deletion/duplication or haplotype analysis, referenced
81479	FSHD panel / other multigene references

Limb-Girdle Muscular Dystrophy panel CPT CodesCPT

81324	Limb Girdle Muscular Dystrophy multigene panel (referenced)
81325	Limb Girdle Muscular Dystrophy multigene panel (referenced)
81448	Limb Girdle Muscular Dystrophy multigene panel (referenced)

Covered CPT Codes (examples shown in text)CPTCovered

81324	Panel/test code referenced for LGMD and related panels
81325	Panel/test code referenced for LGMD and related panels
81448	Comprehensive multigene panel code referenced for multiple panels

Additional Procedure CodesmixedCovered

81234	DMPK repeat analysis mapping
81239	CNBP repeat analysis mapping
81401	Targeted sequencing code referenced
81404	Targeted sequencing code referenced
S3853	HCPCS/other code referenced with repeat analyses

Provider Responsibilities and Authorization Guidance

Prior Authorization

Prior authorization / coding headline

Verify prior authorization (PA) requirements and coding before ordering or submitting claims for the genetic tests and panels referenced in this policy.

Providers should confirm whether PA is required for the specific CPT/HCPCS codes being requested.
Inclusion or exclusion of a code in this policy does not guarantee coverage — check the member’s benefit documents and plan PA rules prior to submission.

Prior Authorization

Epilepsy panel prior authorization

Prior authorization may be required for multigene epilepsy panels and other gene-specific tests listed in this policy. Coverage is limited to medically necessary indications described in the criteria.

Confirm PA requirements for epilepsy multigene panels (including copy number analysis) and for single-gene tests where indicated.
Coverage determinations use the clinical policy’s medical necessity criteria; verify PA submission aligns with those criteria.

Billing Rule

Diagnosis-code alignment and coding mismatch risk

Claims must include mapped procedure codes and matching diagnosis codes and panel identifiers to avoid denials.

Submit the CPT/HCPCS codes that match the performed test and include the appropriate ICD-10 diagnosis code(s) that support medical necessity.
Ensure panel identifiers or test names on the claim match the laboratory report and the PA request to reduce coding mismatch risk.

Documentation Required

Clinical rationale and documentation

Document clinical rationale and family history thoroughly to support medical necessity for the requested genetic test.

Provide a clear clinical rationale describing signs/symptoms, prior diagnostic workup, and how testing will inform management.
Include relevant family history and relationship to any affected relatives when ordering targeted or predictive testing.

Documentation Required

Known familial variant requirement

Targeted mutation analysis for a known familial variant: only medically necessary when the member has a close relative with a known pathogenic/likely pathogenic variant.

When requesting targeted analysis (e.g., single known variant testing), include documentation identifying the affected relative, the relationship, and the variant details (gene, nucleotide/protein change).

Denial Risk

HTT repeat analysis — investigational triggers

HTT (Huntington disease) repeat testing is covered only for the specified clinical indications; testing outside those criteria is investigational and not covered.

HTT repeat analysis (81271, 81274) is medically necessary for symptomatic individuals with compatible features or for predictive testing with appropriate counseling.
Predictive testing must include documented pre- and post-test genetic counseling.

Note

Follow-up for repeat analysis

When repeat molecular genetic testing is used (e.g., DMPK/CNBP for myotonic dystrophy), be aware of false-negative risk and plan for expert referral if clinical suspicion remains high despite negative results.

Repeat or alternative tissue testing and family segregation studies may be necessary for equivocal repeat sizing results.
If clinical features strongly suggest the diagnosis despite negative molecular testing, document the plan for expert referral or further testing.

Prior Authorization

Appropriate first-line test and testing sequence

Order the most appropriate first-line test based on clinical suspicion—single-gene testing may be preferred when a specific disorder is highly suspected.

For suspected dystrophinopathies, deletion/duplication testing (MLPA or CGH) is the recommended first-line test; sequence analysis only if deletion/duplication testing is negative.
For conditions like SMA, DM1/DM2, and others with clear first-line molecular tests, perform those before proceeding to broader panels or invasive testing such as muscle biopsy.

Documentation Required

Exclude alternative causes before testing; required clinical documentation

Exclude alternative causes and document prior diagnostic evaluations where required by the clinical criteria.

For periodic paralysis testing, exclude non-genetic causes of hypokalemia (renal, endocrine, medication/toxin-related) and document results before genetic testing.
Provide the results of prior diagnostic studies (e.g., newborn screen, CK levels, EMG, long exercise test) when applicable to support the requested test.

Documentation Required

Hereditary spastic paraplegia — required documentation

Hereditary spastic paraplegia panels must include specified minimum gene content and clinical features must be documented to meet medical necessity.

Document the member’s lower-extremity spasticity, weakness, hyperreflexia/extensor plantar responses, and any sensory findings.
Ensure the panel includes at least the genes listed in the policy (e.g., SPAST, ATL1, KIF1A, CYP7B1, SPG7, SPG11).

Tests and Indications Considered Not Medically Necessary

This policy maps tests and panels to procedure codes for informational and billing alignment. The document does not provide an explicit stand-alone list of tests that are categorically not covered; instead, coverage determinations are based on whether the submitted test meets the clinical criteria described in the policy and the applicable coding mappings.

Uses of the listed genetic tests or panels that do not meet the specific clinical or family-history criteria in the medically necessary sections are considered investigational and therefore not covered. Providers should ensure that documentation demonstrates the required clinical features or family history before requesting coverage.

Except where a medically necessary indication is explicitly specified, the tests and multigene panels referenced in this policy are considered investigational and not covered. Coverage is limited to the indications and minimum gene content (where stated) outlined in the corresponding covered sections.

Predictive genetic testing of asymptomatic minors for adult-onset conditions is generally inappropriate when early treatment would not alter morbidity or mortality. Predictive testing in asymptomatic minors for adult-onset conditions is typically not covered absent compelling medical benefit; decisions should follow professional guidance and counseling recommendations.

Eligibility and Membership Considerations

Eligibility for covered genetic testing depends on the condition-specific clinical criteria described throughout this policy (for example, symptomatic features, family-history requirements, or minimum panel gene content). The policy contains multiple placeholders and section-specific eligibility statements that must be met for each test request; providers should consult the relevant diagnostic section to confirm which eligibility requirements apply.

Some eligibility statements reference predictive testing pathways and counseling prerequisites (for example, Huntington disease predictive testing requires a presymptomatic individual plus a close relative with a qualifying HTT expansion or a first-degree relative with clinical HD). Review the condition-specific criteria for required family-history documentation and counseling.

Other eligibility language applies when asymptomatic members have a close relative with a known diagnosis (for example, limb-girdle muscular dystrophy panels cover asymptomatic individuals when a close relative is diagnosed but the relative’s genetic status is unavailable). Confirm the exact eligibility conditions in the related panel section before ordering.

Across the policy, general eligibility is anchored to the principle that genetic testing is intended to confirm a diagnosis in symptomatic patients when conventional diagnostic methods have been unsuccessful. Providers should document prior diagnostic efforts and the specific clinical rationale supporting the test request.

For comprehensive neuromuscular panels, eligibility often requires that the patient not have a single-gene disorder that is strongly suspected (where single-gene testing would be preferred) or that prior single-gene testing was non-diagnostic. Follow the stepwise testing preference described in the neuromuscular sections.

Eligibility for inherited peripheral neuropathy panels requires that the member does not already have a clinical diagnosis of Charcot–Marie–Tooth disease or HNPP and that the panel includes the minimum listed genes. Confirm these conditions and panel content in the PMP22/neuropathy section.

Definitions and Key Terms

Indication for testing

Primary indicationGenetic testing used to confirm a diagnosis in symptomatic patients when conventional diagnostic methods have been unsuccessful

Impact on careConfirming a genetic diagnosis may alter management and reduce the need for further diagnostic workup

Appropriate settingTesting intended for hereditary epilepsy, neurodegenerative, and neuromuscular disorders when standard diagnostics are inconclusive

DMPK and CNBP (ZNF9) Repeat Analysis

Test typeDMPK and CNBP (ZNF9) repeat analysis (e.g., 81234, 81239, 81401, 81187) to size CTG/CCTG repeats for DM1/DM2 diagnosis

First-line useRepeat analysis is first-line for suspected DM1 or DM2; muscle biopsy should not be primary diagnostic test when genetic testing is available

Coding mappingsPolicy maps DMPK/CNBP repeat analyses to CPT/HCPCS codes and multigene panel groupings for submission

LRRK2 sequencing/deletion-duplication analysis

Test methodsSequencing and/or deletion/duplication analysis of LRRK2 as part of Parkinson disease genetic evaluation or multigene panel testing

Clinical contextLRRK2 testing considered when genetic diagnosis will inform counseling, prognosis, recurrence risk, or trial eligibility

Coding examplesPolicy maps LRRK2 sequencing/panel testing to multigene panel codes (e.g., 81408, 81479) in coding tables

Known familial variant analysis

DefinitionTargeted mutation analysis for a specific pathogenic or likely pathogenic familial variant when a close relative carries that variant

Coverage requirementMedically necessary only when member has a close relative with a known pathogenic or likely pathogenic variant

Relevant codesExamples include 81403, 81174, 81186, 81190, 81289, 81326, 81337 mapped in policy

Familial ALS (FALS) panel minimum genes

Minimum gene listFamilial ALS panels should include at minimum C9orf72, SOD1, FUS, and TARDBP

Age requirementPanel coverage specified for members 18 years or older when clinical ALS criteria met

Panel codesExamples mapped: 81179, 81403, 81404, 81405, 81406, 81407, 81479, S3800

Close relatives

Close relatives definitionFirst-, second-, and third-degree blood relatives on the same side of the family (first-degree: parents, siblings, children; second-degree: grandparents, aunts/uncles, nieces/nephews, grandchildren, half-siblings; third-degree: great-grandparents, great aunts/uncles, first cousins)

Use in policyDefinition applied to coverage and predictive testing criteria (e.g., known familial variant analysis, HTT predictive testing)

Documentation implicationFamily relationships should be documented when required to meet coverage criteria

Neonate

Neonate definitionA neonate is a baby who is four weeks old or younger

RelevanceUsed to define newborn-screening pathways (e.g., SMA confirmatory testing) and age-based criteria in policy

Clinical implicationNeonatal presentation may trigger specific testing algorithms such as SMN1 confirmatory testing following positive NBS

SMN1/SMN2 testing

SMN1/SMN2 methodsMolecular methods to detect SMN1 deletions and determine SMN2 copy number; used for newborn screening confirmation and diagnosis of spinal muscular atrophy

IndicationsConfirmatory testing following positive newborn screen or symptomatic individuals with SMA features; SMN2 copy number provides prognostic correlation

Coding examplesAssociated codes include 81329, 81336, 81401, 81405, 0236U

Epilepsy multigene panel

DefinitionComprehensive genetic testing for unexplained epilepsy; NSGC recommends panels with >=25 genes and copy number analysis or first-tier exome/genome testing

First-tier recommendationMulti-gene comprehensive testing (exome/genome or multigene panel) is strongly recommended as first-tier for unexplained epilepsy across all ages

Alternate situationsPanels <25 genes may be used in rare situations but require alternate coverage criteria or adjudication

Repeat expansion testing

Repeat expansion testing definitionTargeted analysis (e.g., DMPK, CNBP, HTT) to size pathogenic trinucleotide/tetranucleotide repeats for myotonic dystrophy or Huntington disease

DM1/DM2 thresholdsDM1: >50 CTG repeats in DMPK; DM2: >75 CCTG repeats in CNBP (ZNF9); gray-zone repeats may require tissue testing or segregation studies

Clinical recommendationRepeat expansion analysis is first-line diagnostic test for suspected DM1/DM2 and HTT testing for HD per clinical features or predictive-testing criteria

DM1/DM2 repeat expansions

DM1 pathogenic size>50 CTG repeats indicates DM1 (DMPK) as diagnostic threshold

Clinical useDM1 molecular testing is first-line; muscle biopsy should not be primary diagnostic when suspicion clear; expert referral recommended for false-negatives

Interpretation noteFalse-negative results can occur; family segregation and specialist input may be necessary

Hypokalemic periodic paralysis diagnostic criteria

HypoPP diagnostic potassium thresholdDiagnosis established by two or more attacks with documented serum K+ <3.5 mEq/L (or one attack plus one in relative)

Alternate criteriaOr three or more supportive clinical/lab features (onset first/second decade; attacks >2 hours; triggers; improvement with potassium; family history; positive long exercise test) with exclusion of other causes

Pre-testing requirementExclude alternative causes of hypokalemia (renal, adrenal, thyroid dysfunction; RTA; diuretics/laxatives) before genetic testing

GeneReviews / OMIM

Primary knowledge resourcesGeneReviews and OMIM cited as primary genomic knowledge resources supporting test interpretation and condition-specific guidance

Supporting literaturePolicy references include ACMG technical standards and multiple guideline citations to support testing recommendations

Use in interpretationReferencing these resources is recommended for variant interpretation, testing strategy, and counseling guidance

Background and Rationale

Genetic testing is used to confirm a suspected hereditary diagnosis in patients who present with signs or symptoms and for whom conventional diagnostic approaches have failed to identify the cause. A documented clinical rationale increases the likelihood that a requested test will meet coverage criteria.

Policy Revision History

2023-03policy_development_approvalLatest

Policy developed and approved (internal metadata indicates development and approval in March 2023).

G60.0	Hereditary motor and sensory neuropathy
G60.8	Other hereditary and idiopathic neuropathies
G60.9	Hereditary and idiopathic neuropathy, unspecified
G71.0	Muscular dystrophy
G71.11	Myotonic dystrophy
G20	Parkinson disease
G24.1	Drug-induced dystonia (listed with dystonia panels)

81284	FXN repeat analysis
81285	FXN repeat analysis
0233U	FXN HCPCS

81406	Panel code referenced for congenital myasthenic and other neuromuscular panels
81407	Panel code referenced for congenital myasthenic and other neuromuscular panels
81479	Unlisted molecular pathology code referenced for several panels
81187	Repeat expansion/test code referenced

81185	Comprehensive panel sequencing
81189	Panel sequencing
81286	Sequencing
81403	Targeted mutation analysis
81404	Gene panel
81479	Unlisted molecular pathology procedure
0216U	Panel-specific HCPCS
0217U	Panel-specific HCPCS

81161	DMD sequencing
81405	Sequencing and/or deletion/duplication
81406	Sequencing and/or deletion/duplication
81419	Epilepsy panel
81329	SMN1 sequencing/deletion analysis
81336	SMN1 analysis
81401	SMN2 deletion/duplication
0236U	SMN1 HCPCS

81405	PSEN1 sequencing
81406	PSEN2/APP sequencing
81479	Unlisted molecular pathology
81401	APOE
S3852	APOE specific code
81271	HTT repeat analysis
81274	HTT repeat analysis

81179	FALS panel sequencing
81407	Sequencing
S3800	FALS HCPCS
81324	PMP22 sequencing
81325	PMP22 deletion/duplication
81448	Inherited peripheral neuropathy panel

81234	DMPK repeat analysis
81239	DMPK testing
81401	Repeat expansion testing (DMPK context)
81404	Multigene panel / other molecular testing codes referenced with repeat analysis
S3853	HCPCS for repeat expansion testing (example)
81187	CNBP (ZNF9) repeat analysis

81405	Limb-girdle muscular dystrophy multigene panel
81406	Multigene panel (muscle/neuromuscular)
81407	Multigene panel
81408	Large multigene panel / sequencing
81479	Unlisted molecular pathology procedure (used for some panels)
81448	Multigene panel (general category referenced multiple times)

81406	CACNA1S/SCN4A sequencing or deletion/duplication (periodic paralysis context)
81479	Panel/unlisted molecular pathology (periodic paralysis context)