Centene genetic aortopathy coverage update

Coverage Criteria for Genetic Testing — Aortopathies & Connective Tissue Disorders

Comprehensive Connective Tissue Disorders Multigene Panel

Covered when the member meets criteria for at least one specified disorder.

Comprehensive panel indication: Member meets criteria for at least one of: Marfan syndrome, Loeys-Dietz syndrome, Classic Ehlers-Danlos syndrome (cEDS), Vascular Ehlers-Danlos syndrome (vEDS).

Comprehensive connective tissue disorders multigene panel (CPT 81410, 81411) is investigational for all other indications, including isolated hypermobility/hEDS.

FBN1 Sequencing and/or Deletion/Duplication Analysis

FBN1 sequencing and/or deletion/duplication (81408, 81479) is medically necessary when ANY of the following are present:

Major Marfan features: Member has one or more of: (1) Aortic root enlargement (Z-score ≥ 2.0) or aortic dissection; OR (2) Ectopia lentis; OR (3) A systemic score ≥ 7 using the listed Marfan systemic features.Z-score ≥ 2.0 for aortic root enlargement

FBN1 sequencing and/or deletion/duplication analysis is investigational for other indications.

Loeys-Dietz Syndrome Multigene Panel

Loeys-Dietz multigene panel (81405, 81408, 81479) is medically necessary when the member meets at least two of the following:

LDS clinical criteria: Member has at least two of: characteristic facial features (e.g., widely spaced eyes, craniosynostosis); bifid uvula or cleft palate; tortuosity of the aorta and its branches; aortic dilatation or dissection; joint hypermobility; OR a first-degree relative with a clinical diagnosis of Loeys-Dietz syndrome.2

Loeys-Dietz multigene panel analysis is investigational for other indications.

Familial Thoracic Aortic Aneurysm and Dissection (TAAD) Multigene Panel

TAAD multigene panel (81405, 81406, 81408, 81410, 81411, 81479) is medically necessary when ALL of the following are met:

TAAD criteria: A) Member has a history of one or more of: aortic root enlargement, thoracic aortic aneurysm, or type A or type B aortic dissection; AND B) Member does not meet diagnostic criteria for another connective tissue disorder; AND C) Member has a family history of aortic root dilation or dissection consistent with autosomal dominant inheritance.

Multigene panels including HTAD-associated genes are recommended per guidelines; panels are investigational for other indications.

Classic Ehlers-Danlos Syndrome (cEDS) Multigene Panel

Classic Ehlers-Danlos syndrome multigene panel (81408, 81479) is medically necessary when ALL of the following are met:

cEDS criteria: A) Skin hyperextensibility and atrophic scarring; AND B) Member has generalized joint hypermobility OR at least three of the listed minor features (e.g., easy bruising, skin fragility, soft/doughy skin, molluscoid pseudotumors, subcutaneous spheroids, epicanthal folds, family history of a first-degree relative with cEDS, complications of joint hypermobility); AND C) Panel includes, at minimum, COL5A1 and COL5A2 (sequence analysis recommended first per GeneReviews).

cEDS panel analysis is investigational for other indications including isolated hypermobility/hEDS.

COL3A1 Sequencing and/or Deletion/Duplication Analysis

COL3A1 sequencing and/or deletion/duplication analysis (81479) is medically necessary when ANY of the following are present:

vEDS major/minor features: Member meets any of: arterial rupture or dissection under age 40; spontaneous sigmoid colon perforation without known diverticular disease; uterine rupture in the third trimester without prior cesarean; carotid-cavernous sinus fistula without trauma; a close relative with a clinical diagnosis of vEDS; OR at least two minor criteria from the listed features (e.g., unexplained bruising, thin translucent skin, spontaneous pneumothorax, characteristic facial appearance, tendon/muscle rupture, gingival fragility, keratoconus, early-onset varicose veins).

If no variant found on sequencing, CNV detection (deletion/duplication analysis) is recommended; testing investigational for other indications.

Other Covered Connective Tissue Disorders

Genetic testing to establish or confirm other listed connective tissue disorders may be medically necessary due to rarity when clinical features or family history are consistent with the disorder.

Other disorders: Conditions with known genetic association (e.g., arthrochalasia EDS, brittle cornea syndrome, dermatosparaxis EDS, kyphoscoliotic EDS, musculocontractural EDS, myopathic EDS, spondylodysplastic EDS, periodontal EDS, cardiac-valvular EDS) when clinical features are consistent and testing is intended to establish or confirm diagnosis.

Tests not specifically discussed will be evaluated per the General Approach to Genetic and Molecular Testing.

Coverage criteria for connective tissue disorder testing

Covered when clinical features and/or family history indicate a likely connective tissue disorder and testing is intended to establish or confirm diagnosis.

General coverage conditions: Genetic testing to establish or confirm diagnosis of connective tissue disorders (including listed EDS subtypes, Marfan syndrome, Loeys-Dietz syndrome, TAAD/HTAD, and other related conditions) is considered medically necessary when the member demonstrates clinical features consistent with the disorder or relevant family history as outlined in GeneReviews, AHA/ACC, ACMG, and International EDS Consortium guidance.

See specific disorder nodes for disorder-specific criteria.

Marfan syndrome (FBN1): Testing (FBN1 sequencing and/or deletion/duplication analysis) is indicated when diagnostic criteria are met, such as aortic root enlargement with Z-score >2.0, ectopia lentis, systemic score ≥7, or identification of a pathogenic FBN1 variant in a proband.Z-score >2.0

GeneReviews supports sequencing first and consideration of multigene panels when phenotype suggests multiple genes.

Loeys-Dietz syndrome:

Updated coverage criteria groups

Policy criteria updated for several genetic testing categories.

FBN1 testing: FBN1 sequencing and/or deletion/duplication criteria expanded to cover individuals with a clinical diagnosis of Marfan syndrome.

Aligned with updated guidance and GeneReviews.

Multigene panels (Loeys-Dietz, TAAD): Minimum gene lists removed; panels will be evaluated without pre-specified minimum gene lists to allow current market offerings.

Provides operational flexibility for panel composition.

Classic EDS testing: Sequence analysis of COL5A1 and COL5A2 (and sometimes COL1A1 on panels) is noted as first-line testing for cEDS per GeneReviews.

Reflects GeneReviews guidance and recent updates.

Per policy language, genetic testing is considered investigational and not covered for isolated joint hypermobility and for hypermobile Ehlers-Danlos syndrome (hEDS), because the causative gene(s) for hEDS are currently unknown and the diagnosis is made clinically rather than by molecular testing. Comprehensive connective tissue disorder panels are investigational for indications outside the specified disorder criteria, including isolated hypermobility/hEDS.

Operational criteria were updated to remove explicit minimum gene lists from several multigene panel criteria. Tests that do not meet the updated disorder-specific criteria — or that fall outside the scope of the policy’s General Approach to Genetic and Molecular Testing — may be subject to review or denial under the plan’s medical necessity determinations.

The policy scope was revised to remove hypermobile Ehlers-Danlos syndrome (hEDS) from prior listed testing recommendations. The document reiterates that hEDS is a clinical diagnosis per GeneReviews and therefore is not an indication for routine genetic testing.

Each genetic test and panel described in the policy is considered investigational (not medically necessary) when used for indications other than the specific, criteria-defined purposes listed in the policy. Providers should confirm that the member meets the disorder-specific clinical or family-history criteria before ordering covered testing.

Comprehensive Ehlers-Danlos Syndrome Multigene Panels were removed from the policy’s coverage criteria reference table during this revision. Such panels will be evaluated under the updated policy approach and the General Approach to Genetic and Molecular Testing rather than by the removed reference listing.

Coverage and denial determinations in this policy are grounded in medical necessity. Tests that do not meet the policy’s medical necessity criteria — including those outside the stated disorder-specific indications or General Approach — may be considered not covered under the plan’s terms, conditions, exclusions, and limitations.

Indications Covered by This Policy

Establishing or confirming a genetic diagnosis for specified connective tissue disorders

Establishing or confirming a genetic diagnosis for specified connective tissue disorders when clinical criteria are met.

Covered indications list: Establishing or confirming genetic diagnosis for Marfan syndrome, Loeys-Dietz syndrome, TAAD/HTAD, classic Ehlers-Danlos syndrome, vascular Ehlers-Danlos syndrome, and other listed rare connective tissue disorders when disorder-specific clinical criteria are satisfied.

See individual disorder criteria and GeneReviews references for detailed clinical thresholds.

Establishing or confirming diagnosis when clinical criteria or family history are suggestive

Establishing or confirming diagnosis of Marfan syndrome, Loeys-Dietz syndrome, TAAD/HTAD, classic and vascular Ehlers-Danlos syndromes, and other connective tissue disorders when clinical criteria or family history are suggestive.

General guidance for testing: Genetic testing is considered medically necessary when clinical features and/or relevant family history suggest a connective tissue disorder and testing is intended to establish or confirm diagnosis; disorder-specific minimal criteria and GeneReviews/ guideline references are used to determine eligibility.

Coding and Billing

Referenced CPT CodesCPT

81410	Comprehensive connective tissue disorders multigene panel
81411	Comprehensive connective tissue disorders multigene panel (higher gene count)
81408	Targeted gene sequencing and/or deletion/duplication analysis (e.g., FBN1)
81479	Unlisted molecular pathology procedure (used for some single-gene analyses, e.g., COL3A1)
81405	Targeted multigene panel (used for Loeys-Dietz, TAAD panels)
81406	Targeted multigene panel (used for TAAD panels)
81400	Single gene sequencing (other covered connective tissue disorders)
81401	Single gene sequencing (other covered connective tissue disorders)
81402	Single gene sequencing (other covered connective tissue disorders)
81403	Single gene sequencing (other covered connective tissue disorders)

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Referenced ICD CodesICD-10

I71.00-I71.9	Thoracic aortic aneurysm and dissection (range) referenced as common ICD codes
M35.7	Ehlers-Danlos syndrome
Q79.60-Q79.69	Congenital musculoskeletal anomalies / EDS-related codes
Q12.1	Congenital malformation of the aorta (referenced)
Q87.4	Congenital malformation syndromes predominantly affecting facial appearance
Q87.5	Other congenital malformation syndromes predominantly affecting limbs and musculoskeletal system (used for TAAD)
Q79.63	Ehlers-Danlos syndrome specific code (referenced)

Covered CPT Codes (panel codes referenced)CPTCovered

81400	Molecular pathology procedure or multigene panel (as listed in document)
81401	Molecular pathology procedure or multigene panel (as listed in document)
81402	Molecular pathology procedure or multigene panel (as listed in document)
81403	Molecular pathology procedure or multigene panel (as listed in document)
81404	Molecular pathology procedure or multigene panel (as listed in document)
81405	Molecular pathology procedure or multigene panel (as listed in document)
81406	Molecular pathology procedure or multigene panel (as listed in document)
81407	Molecular pathology procedure or multigene panel (as listed in document)
81408	Molecular pathology procedure or multigene panel (as listed in document)

CPT coding presentation updated to individual codesCPT

No codes listed

inv-20: Aortic root enlargement (Marfan systemic criteria) — Z-score of 2 or greater

CriterionAortic root enlargement defined as Z-score of 2 or greater

ContextOne of the major indications for FBN1 sequencing and/or deletion/duplication to confirm Marfan syndrome

Associated testsFBN1 sequencing and/or deletion/duplication (CPT 81408, 81479)

inv-21: Aortic root enlargement Z-score — Z-score >2.0

ThresholdAortic root enlargement Z-score >2.0

Normalization

Provider Actions, Prior Authorization, and Documentation

Prior Authorization

Prior Authorization Required

Prior authorization is required for multigene connective tissue disorder panels (e.g., CPT 81405, 81406, 81410, 81411 where applicable) when used to establish or confirm a diagnosis. Follow the Health Plan’s prior authorization procedures and submit supporting clinical documentation per plan-specific requirements.

Affected CPT examples: 81405, 81406, 81408, 81410, 81411
Submit prior auth per payer procedures before testing

Denial Risk

Tests Subject to Review or Denial

Tests that do not meet the updated policy criteria or that do not include the expected minimum gene content (when a minimum list is specified) may be subject to review or denial. Coverage is determined per the plan’s coverage documents and may be limited by state-specific requirements or exclusions.

Tests Not Covered / Investigational

Testing solely to evaluate for hypermobile Ehlers-Danlos syndrome (hEDS) is not covered because, per GeneReviews, the gene(s) associated with hEDS are currently unknown and hEDS remains a clinical diagnosis. Therefore, molecular testing aimed only at diagnosing hEDS is considered inappropriate and not medically necessary.

Comprehensive Ehlers-Danlos Syndrome Multigene Panels were removed from the coverage criteria reference table. The policy now evaluates panels and single-gene tests according to the updated disorder-specific criteria and the General Approach to Genetic and Molecular Testing rather than relying on the removed comprehensive-panel listing.

Previous requirements that tied coverage to specific tests or minimum gene lists have been removed. The policy now assesses tests (including those related to hypermobile EDS considerations) based on the updated criteria and the General Approach, rather than enforcing prior minimum-gene-list-dependent rules.

Background and Rationale

Hereditary connective tissue disorders frequently affect multiple organ systems including the cardiovascular system; their clinical features can overlap and genetic heterogeneity is common. Identification of a genetic diagnosis can change management such as aortic surveillance and surgical planning. The policy notes that hEDS is diagnosed clinically and is not currently amenable to diagnostic genetic testing.

For the purposes of family-history-based coverage decisions, close relatives include first-, second-, and third-degree blood relatives. First-degree relatives are parents, siblings, and children.

For classic Ehlers-Danlos syndrome (cEDS), sequence analysis of COL5A1 and COL5A2 is performed first to detect point variants and small intragenic changes; multigene panels may also include COL1A1 and other EDS-related genes per GeneReviews guidance.

The policy recommends sequencing approaches in certain clinical situations. For example, if both aortic root enlargement and ectopia lentis are present, FBN1 testing should be included in the panel or have been previously performed with negative results; GeneReviews supports targeted sequencing of primary genes (e.g., FBN1) before broader testing in many cases.

Definitions

inv-36: Close relatives

DefinitionClose relatives include first-, second-, and third-degree blood relatives

First-degreeParents, siblings, and children

Second-degreeGrandparents, aunts, uncles, nieces, nephews, grandchildren, and half-siblings

Third-degreeGreat-grandparents, great aunts/uncles, great grandchildren, and first cousins

inv-37: Type A/Type B aortic dissection

Type AAortic dissections that occur in the ascending aorta, near where it branches off the heart

Type B

Member Eligibility and Test Eligibility Requirements

Eligibility requirement items are referenced in the policy structure; specific top-level eligibility nodes were not included in this extract but disorder-specific clinical criteria and family-history elements determine eligibility for covered testing.

Additional eligibility items are managed within the disorder-specific criteria; the policy cross-references GeneReviews, guideline criteria, and the General Approach to Genetic and Molecular Testing to define precise eligibility for testing.

Eligibility for some panels depends on a combination of clinical features and family history; the updated policy consolidates known familial-variant criteria into the General Approach to Genetic and Molecular Testing.

Eligibility considerations and sequencing priorities (for example, known familial variant testing versus broader panels) are addressed in the General Approach and disorder-specific sections rather than by fixed minimum gene lists.

Eligibility details for rare connective tissue disorders and HTAD-related testing are embedded in the updated criteria; reviewers should consult the disorder-specific sections and the General Approach for full requirements.

Revision History and Policy Changes

04/24policy_revision

Updated title to reflect V2.2024; consolidated known familial variant criteria into the General Approach to Genetic and Molecular Testing; expanded FBN1 criteria to allow coverage for individuals with a clinical diagnosis of Marfan syndrome; removed minimum gene lists from Loeys‑Dietz and TAAD multigene panel criteria; removed COL1A1 from the cEDS minimum list.

03/23policy_revision

Semi‑annual review and updates: updated title to V1.2024, revised overview, coding table, background and references; removed Comprehensive Ehlers‑Danlos Syndrome Multigene Panels from the coverage criteria reference table and adjusted wording regarding isolated hypermobility.

11/24policy_revision

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Genetic Testing: Aortopathies and Connective Tissue Disorders