CurrentWellCarePolicy N/A

Genetic Testing: Dermatologic Conditions

Defines medical necessity and investigational indications for genetic and molecular testing to establish or confirm diagnoses of inherited dermatologic conditions for members of WellCare-affiliated health plans.

Policy Summary

PayerWellCare

PolicyGenetic Testing: Dermatologic Conditions

Policy CodePolicy N/A

Change TypeNo material changes

Effective DateN/A

Next Review DateN/A

Key ActionObtain prior authorization for the specific genetic tests when used to establish or confirm diagnoses per the policy criteria.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

multiplePanel types referenced

81403Known familial variant code

3Diseases covered (excerpt)

12ARCI genes listed

3/1/2023Last review

Coverage Criteria for Genetic Testing

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Known Familial Variant Analysis (81403)

Covered when ALL of the following are met for Known Familial Variant Analysis:

Known Familial Variant Analysis: The member has a close relative with a known pathogenic or likely pathogenic variant causing the dermatologic condition; AND the test requested is targeted mutation analysis (CPT 81403).

Targeted mutation analysis (81403) is considered investigational for all other indications.

Congenital Ichthyosis Multigene Panel (81405, 81479, 81252)

Covered when ALL of the following are met for Congenital Ichthyosis Multigene Panel:

Congenital Ichthyosis Panel: Member has scaly skin with or without history of harlequin ichthyosis, collodion membrane, or thick hyperkeratotic skin; AND one or more of: ectropion, eclabium, scarring alopecia, palmar/plantar hyperkeratosis, or erythroderma; AND the panel includes at minimum ABCA12, SLC27A4, and TGM1; AND the requested test is a multigene panel (CPTs 81405, 81479) or targeted sequencing (81252).

Multigene panel testing for congenital ichthyosis is investigational for indications not meeting these criteria.

RASA1 and EPHB4 Sequencing/Deletion-Duplication or Multigene Panel (81479)

Covered when ANY of the following clinical features are present for RASA1/EPHB4 testing:

CM-AVM indications: Member displays one or more of: capillary malformations, arteriovenous malformations/arteriovenous fistulas, or Parkes Weber syndrome phenotype; AND testing is RASA1 and/or EPHB4 sequencing and/or deletion/duplication analysis or a multigene panel (CPT 81479).

RASA1/EPHB4 testing is investigational for other indications; panels including EPHB4 and RASA1 are recommended per GeneReviews.

Epidermolysis Bullosa Multigene Panel (81406, 81479)

Covered when ALL of the following are met for Epidermolysis Bullosa Multigene Panel:

Epidermolysis Bullosa Panel: Member has skin fragility manifested by blistering with little or no trauma; AND presence of blistering that may be neonatal, primarily affects hands/feet or whole body, occurs in annular/curvilinear groups, can lead to progressive pigmentation changes, or is associated with severe palmar/plantar hyperkeratosis; AND one or more associated findings such as nail dystrophy, milia, congenital pyloric atresia, or ureteral/renal anomalies; AND the panel includes at minimum EXPH5, KRT5, KRT14, and PLEC; AND testing is multigene panel sequencing/deletion-duplication (CPTs 81406, 81479).

Multigene panel testing for epidermolysis bullosa is investigational for indications not meeting these criteria.

Other Covered Dermatologic Conditions

Covered when ALL of the following are met for other rare dermatologic conditions:

Other covered dermatologic conditions: Genetic testing to establish or confirm a listed rare dermatologic condition is medically necessary when the member demonstrates clinical features consistent with the condition (examples include Hidrotic Ectodermal Dysplasia 2, Hypohidrotic Ectodermal Dysplasia, ocular albinism X-linked, and oculocutaneous albinism); AND testing is targeted to the genes/panels appropriate for the suspected disorder.

Conditions not specifically listed will be evaluated per the General Approach to Genetic Testing policy; see referenced resources (GeneReviews, OMIM) for disorder-specific clinical features.

CM-AVM diagnostic criteria

Covered when ALL of the following are met:

CM-AVM diagnostic requirement: Proband has suggestive clinical findings (multifocal capillary malformations and/or AVMs/AVFs or Parkes Weber phenotype) AND molecular genetic testing identifies a heterozygous pathogenic variant in EPHB4 or RASA1 establishing the diagnosis.

Use of multigene panels that include EPHB4 and RASA1 is recommended per GeneReviews; panels may limit incidental findings and cost.

Autosomal recessive congenital ichthyosis (ARCI) diagnostic criteria

Covered when ANY of the following are met:

ARCI molecular diagnosis: Identification of biallelic pathogenic variants in one of the ARCI-associated genes (ABCA12, ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, TGM1) establishes the diagnosis; a multigene panel including these genes is the diagnostic test of choice; if unavailable, single-gene testing may be considered (e.g., ABCA12 for harlequin ichthyosis, TGM1 for non-harlequin ARCI, SLC27A4 for ichthyosis-prematurity syndrome).

Panels that include the 12 ARCI genes are preferred to limit variants of uncertain significance and to increase diagnostic yield.

Epidermolysis bullosa diagnostic criteria

Covered when ALL of the following are met:

EBS molecular diagnosis: Proband has clinical features consistent with epidermolysis bullosa (skin fragility with blistering and supporting signs) AND identification of pathogenic variants in the relevant genes (biallelic variants in EXPH5 or TGM5, or heterozygous — or rarely biallelic — variants in KRT5 or KRT14) by molecular genetic testing; multigene panels including EXPH5, KRT5, KRT14, TGM5 and other relevant genes may be used.

Absence of a known family history does not preclude the diagnosis; testing approach per GeneReviews.

Any genetic test request that does not meet the specific clinical criteria outlined for the covered indications in this policy (including targeted familial variant analysis under CPT 81403 and multigene panel testing such as CPTs 81405, 81406, 81479, and 81252) is considered investigational and not covered. The policy’s covered indications require the presence of the defined clinical features and gene/panel composition described for each condition (e.g., known familial pathogenic variant in a close relative for targeted analysis; phenotype and minimum gene sets for congenital ichthyosis and epidermolysis bullosa).

Providers should confirm that the request aligns with the condition-specific criteria (for example, documented close relative with a known pathogenic or likely pathogenic variant for familial testing, or the required phenotype and panel gene content for congenital ichthyosis and epidermolysis bullosa) before submission, because testing outside those criteria may be denied as investigational.

Coverage of genetic and molecular testing is subject to the member’s specific plan exclusions, terms, limitations, and any applicable state Medicaid or Medicare rules. The Health Plan’s coverage documents, contract language, and administrative policies govern payment and may limit or exclude coverage even when testing meets clinical criteria in this policy.

Targeted mutation analysis (e.g., CPT 81403) and multigene panel testing (e.g., CPTs 81405, 81406, 81479, 81252) are considered investigational and not medically necessary when used for indications other than those explicitly listed in this policy. Requests for familial variant testing without a documented close relative having a known pathogenic or likely pathogenic variant, or panel testing for phenotypes not meeting the condition-specific criteria, will be evaluated as investigational.

Specific Covered Indications

Known familial pathogenic or likely pathogenic variant present in a close relative — targeted mutation analysis (81403).

Known familial pathogenic or likely pathogenic variant present in a close relative — targeted mutation analysis (81403).: See criteria for Known Familial Variant Analysis: close relative with documented pathogenic or likely pathogenic variant and use of CPT 81403.

Documentation should establish family relationship (close relative defined as first-, second-, or third-degree).

Congenital ichthyosis with specified clinical features — multigene panel including ABCA12, SLC27A4, TGM1 (81405, 81479, 81252).

Congenital ichthyosis with specified clinical features — multigene panel including ABCA12, SLC27A4, TGM1 (81405, 81479, 81252).: Member meets the congenital ichthyosis panel criteria (scaly skin with/without harlequin ichthyosis, collodion membrane, or thick hyperkeratotic skin, plus one or more key features such as ectropion or erythroderma) AND the panel includes at minimum ABCA12, SLC27A4, and TGM1. Multigene panel testing (81405, 81479) or targeted testing (81252) may be used.

If a multigene panel including the diagnostically relevant genes is unavailable, single-gene testing (e.g., ABCA12, TGM1, SLC27A4) may be considered based on phenotype.

Capillary malformation-arteriovenous malformation (CM-AVM) phenotype — RASA1 and EPHB4 sequencing and/or deletion/duplication or multigene panel (81479).

Capillary malformation-arteriovenous malformation (CM-AVM) phenotype — RASA1 and EPHB4 sequencing and/or deletion/duplication or multigene panel (81479).: Member displays capillary malformations, AVMs/AVFs, or Parkes Weber phenotype; testing should include sequencing and/or deletion/duplication analysis of RASA1 and EPHB4 or a multigene panel that includes these genes per GeneReviews recommendations.

Diagnosis is established by a heterozygous pathogenic variant in EPHB4 or RASA1.

Epidermolysis bullosa with described clinical presentation — multigene panel including EXPH5, KRT5, KRT14, PLEC (81406, 81479).

Epidermolysis bullosa with described clinical presentation — multigene panel including EXPH5, KRT5, KRT14, PLEC (81406, 81479).: Member meets clinical criteria for epidermolysis bullosa (skin fragility with blistering as described) AND the panel includes at minimum EXPH5, KRT5, KRT14, and PLEC; multigene panel testing (81406, 81479) is appropriate to establish the diagnosis.

Multigene panels that include additional relevant genes may be used per GeneReviews guidance.

Other rare dermatologic genetic conditions when clinical features are consistent (examples listed).

Other rare dermatologic genetic conditions when clinical features are consistent (examples listed).: Member demonstrates clinical features consistent with a listed rare dermatologic genetic condition (examples: Hidrotic Ectodermal Dysplasia 2, Hypohidrotic Ectodermal Dysplasia, ocular albinism X-linked, oculocutaneous albinism) AND testing is targeted to the genes/panels appropriate for that condition.

If the condition is not specifically discussed in this policy, evaluate per the General Approach to Genetic Testing policy.

Suspected CM-AVM syndrome with compatible capillary malformations and/or AVMs/AVFs or Parkes Weber phenotype; molecular testing for EPHB4 or RASA1.

Suspected CM-AVM syndrome with compatible capillary malformations and/or AVMs/AVFs or Parkes Weber phenotype; molecular testing for EPHB4 or RASA1.: Proband has clinical features suggestive of CM-AVM (multifocal capillary malformations, AVMs/AVFs, or Parkes Weber phenotype) AND molecular genetic testing targets EPHB4 and RASA1 (sequencing and/or deletion/duplication) or a multigene panel including these genes.

Diagnosis established by identification of a heterozygous pathogenic variant in EPHB4 or RASA1.

Suspected autosomal recessive congenital ichthyosis (ARCI) based on neonatal presentation or phenotype; multigene panel including the 12 ARCI genes or targeted single-gene testing per phenotype.

Suspected autosomal recessive congenital ichthyosis (ARCI) based on neonatal presentation or phenotype; multigene panel including the 12 ARCI genes or targeted single-gene testing per phenotype.: Identification of biallelic pathogenic variants in one of the 12 ARCI-associated genes (ABCA12, ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, TGM1) establishes the diagnosis; if a multigene panel is unavailable, consider single-gene testing (ABCA12 for harlequin ichthyosis, TGM1 for other ARCI presentations, SLC27A4 for ichthyosis-prematurity syndrome).

A multigene panel including these genes is the diagnostic test of choice.

Suspected epidermolysis bullosa (including EBS and EB-PA) with compatible clinical features; multigene panel including EXPH5, KRT5, KRT14, TGM5 and others as appropriate.

Suspected epidermolysis bullosa (including EBS and EB-PA) with compatible clinical features; multigene panel including EXPH5, KRT5, KRT14, TGM5 and others as appropriate.: Proband has clinical features of epidermolysis bullosa (skin fragility with blistering, possible neonatal presentation, palmar/plantar hyperkeratosis, nail dystrophy, milia, family history consistent with AR or AD inheritance, or features of EB-PA such as congenital pyloric atresia and urinary/renal anomalies) AND molecular testing identifies pathogenic variants as specified (biallelic in EXPH5 or TGM5 or heterozygous in KRT5 or KRT14) using a multigene panel that includes EXPH5, KRT5, KRT14, TGM5 and other relevant genes.

Absence of known family history does not preclude testing; panels per GeneReviews are recommended.

Provider Actions, Documentation, and Prior Authorization

Prior Authorization

Prior Authorization Required

Prior Authorization is required for the specific genetic tests listed in this policy when used to establish or confirm a diagnosis (for example, multigene panels and targeted familial variant analysis CPT codes such as 81401–81408, 81479, 81405, 81406, 81403, 81252 where applicable). Prior authorization requirements may vary by member plan; confirm authorization prior to testing.

Affected example CPT groups: 81401–81408, 81479, 81405, 81406, 81403, 81252

Note

Coverage Subject to Plan Terms

Coverage determinations are made in accordance with the member’s benefit plan and are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy contract). Failure to follow plan administrative requirements (including prior authorization and documentation submission rules) may affect coverage.

Documentation Required

Documentation Requirements

Documentation submitted with the request should support that the individual (proband) has clinical features suggestive of the condition under consideration and should include the clinical rationale for testing (for example, signs and symptoms described for congenital ichthyosis, epidermolysis bullosa, or CM‑AVM in GeneReviews). When claiming testing for a known familial variant, documentation must establish the family relationship to the affected relative (close relative defined as first, second, or third‑degree).

Clinical documentation should describe proband signs/symptoms and the diagnostic question being addressed.
When requesting targeted familial variant analysis, include documentation showing the relative with the known pathogenic/likely pathogenic variant and the familial relationship (first–third degree).

Note

When a Multigene Panel Is Not Available

If an indicated multigene panel is not available, single‑gene testing may be acceptable per the clinical guidance (for congenital ichthyosis consider ABCA12 for harlequin ichthyosis, TGM1 for ARCI without harlequin presentation, or SLC27A4 for ichthyosis‑prematurity syndrome).

Single‑gene testing examples: ABCA12, TGM1, SLC27A4

Note

Other Provider Actions

No additional provider actions beyond those noted above are specified in this policy section.

Key Definitions

Close relative — definition and relevance

DefinitionClose relatives include first-, second-, and third-degree blood relatives (first-degree: parents, siblings, children; second-degree: grandparents, aunts/uncles, nieces/nephews, grandchildren, half-siblings; third-degree: great grandparents, great aunts/uncles, great grandchildren, first cousins).

Use for familial variant claimsA documented close relative (first-, second-, or third-degree) with a known pathogenic or likely pathogenic variant is required to support targeted familial variant analysis (CPT 81403).

Documentation expectationFamily relationship should be established in the medical record when claiming known familial variant testing.

CM-AVM syndrome — definition and diagnostic context

Syndrome definitionCapillary Malformation–Arteriovenous Malformation (CM-AVM) syndrome is characterized by multifocal capillary malformations often in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVFs), and can include a Parkes Weber phenotype with limb overgrowth and multiple micro-AVFs.

Diagnostic criteriaDiagnosis is established in a proband with suggestive clinical findings (e.g., multifocal atypical capillary malformations, AVMs/AVFs, or Parkes Weber phenotype) PLUS a heterozygous pathogenic variant in EPHB4 or RASA1 identified by molecular genetic testing.

Testing approachMolecular genetic testing may use multigene panels that include EPHB4 and RASA1 to identify the genetic cause while limiting variants of uncertain significance.

Autosomal recessive congenital ichthyosis (ARCI) — definition and phenotype spectrum

DefinitionAutosomal recessive congenital ichthyosis (ARCI) encompasses a spectrum of nonsyndromic ichthyosis phenotypes ranging from harlequin ichthyosis to lamellar ichthyosis and congenital ichthyosiform erythroderma; severity and presentation vary along a continuum.

Molecular diagnosisDiagnosis is established by identification of biallelic pathogenic variants in one of the ARCI-associated genes (12 genes: ABCA12, ALOX12B, ALOXE3, CASP14, CERS3, CYP4F22, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, TGM1).

Testing recommendationA multigene panel that includes these 12 genes is the diagnostic test of choice; if unavailable, single-gene testing may be considered guided by phenotype (e.g., ABCA12 for harlequin ichthyosis, TGM1 for non-harlequin ARCI, SLC27A4 for ichthyosis-prematurity syndrome).

Epidermolysis bullosa simplex (EBS) — definition and typical gene causes

DefinitionEpidermolysis bullosa simplex (EBS) is a blistering disorder characterized by skin fragility and blistering with little or no trauma; it may present in the neonatal period or later and often affects hands and feet but can be generalized.

Typical gene causesMolecular diagnosis is established by identification of biallelic pathogenic variants in EXPH5 or TGM5, or heterozygous (occasionally biallelic) pathogenic variants in KRT5 or KRT14; panels often include EXPH5, KRT5, KRT14, TGM5 and others.

Clinical features supporting testingFeatures that support suspicion include blistering that may be neonatal, annular/clustered distribution, palmar/plantar hyperkeratosis, nail dystrophy, milia, and a family history consistent with autosomal dominant or recessive inheritance (absence of family history does not preclude diagnosis).

Eligibility Requirements

For targeted familial variant analysis (CPT 81403), the member must have a documented close relative with a known pathogenic or likely pathogenic variant causing the relevant dermatologic condition. Close relatives are defined as first-, second-, or third-degree blood relatives (for example, parents, siblings, children, grandparents, aunts/uncles, nieces/nephews, and first cousins).

Documentation establishing the family relationship and the relative’s molecular result must be provided when submitting requests for known familial variant testing to support medical necessity.

For congenital ichthyosis panel testing (CPTs 81405, 81479, 81252): the member must have scaly skin with or without history of harlequin ichthyosis, collodion membrane, or thick hyperkeratotic skin, and at least one of the listed clinical features (for example, ectropion, eclabium, scarring alopecia, palmar/plantar hyperkeratosis, or erythroderma). The panel must include, at minimum, the genes ABCA12, SLC27A4, and TGM1.

When a suitable multigene panel that includes the required genes is not available, single-gene testing may be considered; starting points include ABCA12 for harlequin ichthyosis, TGM1 for ARCI without harlequin presentation at birth, and SLC27A4 for ichthyosis‑prematurity syndrome.

For suspected CM‑AVM syndrome, testing (sequencing and/or deletion/duplication or multigene panel; CPT 81479) is indicated when the proband displays one or more relevant findings such as capillary malformations, arteriovenous malformations/fistulas, or a Parkes Weber phenotype. Panels should include RASA1 and EPHB4, and diagnosis is established by identifying a heterozygous pathogenic variant in one of these genes.

Documentation of the proband’s compatible clinical findings is required to support medical necessity for CM‑AVM molecular testing.

81403	Targeted mutation analysis (known familial variant)
81405	Multigene sequencing panel (example: congenital ichthyosis)
81406	Multigene sequencing panel (example: epidermolysis bullosa)
81479	Unlisted molecular pathology procedure (used for some panels / sequencing & deletion/duplication)
81252	Specific gene or portion of gene sequencing (listed with ichthyosis panels in document)
81401-81408	Range of molecular pathology codes referenced as covered for dermatologic conditions

Q27.3	ICD-10 code referenced for vascular malformation (as example)
Q27.9	ICD-10 code referenced
Q80	ICD-10 code referenced for ichthyosis
Q81	ICD-10 code referenced for epidermolysis bullosa

OpenPayer

Genetic Testing: Dermatologic Conditions

Coverage Criteria for Genetic Testing

Specific Covered Indications

Coding and Billing

Provider Actions, Documentation, and Prior Authorization

Key Definitions

Background and Rationale

Eligibility Requirements

Not Covered / Investigational