Concert Genetics Genetic Testing: Aortopathies and Connective Tissue Disorders
V2.2024
Date of Last Revision: 04/24

Revision log
Coding Implications

CONCERT GENETICS GENETIC TESTING: AORTOPATHIES AND CONNECTIVE TISSUE DISORDERS

See [Important Reminder](at the end of this policy for important regulatory and legal information.)

OVERVIEW

Hereditary connective tissue disorders are a group of disorders that affect the connective tissues that support the skin, bones, joints, heart, blood vessels, eyes, and other organs. While specific features vary by type, an unusually large range of joint movement (hypermobility) and cardiovascular disease (such as thoracic aortic aneurysms and dissections) are features that are present in many hereditary connective tissue disorders. Medical management may differ based on the underlying genetic etiology. A diagnosis may be made based on clinical examination; however, it can be difficult to reliably diagnose a hereditary connective tissue disorder based on clinical and family history alone.

Accurate diagnosis of a hereditary connective tissue disorder can lead to changes in clinical management, including surveillance of the aorta, surgical repair of the aorta, when necessary, pharmacologic management, as well as surveillance for multisystem involvement in syndromic conditions with risk for thoracic aortic aneurysms and dissection.

Of note, per [GeneReviews](hypermobile Ehlers-Danlos syndrome (hEDS) is based entirely on clinical evaluation and family history and not genetic testing, as the gene(s) associated with hEDS are currently unknown. Therefore, clinical genetic testing for the sole purpose of evaluating for hEDS is not appropriate at this time. Genetic evaluation for other types of EDS are addressed within this policy.

1

Concert Genetics Genetic Testing: Aortopathies and Connective Tissue Disorders
V2.2024
Date of Last Revision: 04/24

POLICY REFERENCE TABLE

Coding Implications

This clinical policy references Current Procedural Terminology (CPT®). CPT is a registered trademark of the American Medical Association. All CPT codes and descriptions are copyrighted 2022, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from the current manuals and those included herein are not intended to be all-inclusive and are included for informational purposes only. Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services.

The tests and associated laboratories and CPT codes contained within this document serve only as examples to help users navigate claims and corresponding criteria; as such, they are not comprehensive and are not a guarantee of coverage or non-coverage. Please see the [Concert Genetics Platform](for a comprehensive list of registered tests.

2

Concert Genetics Genetic Testing: Aortopathies and Connective Tissue Disorders
V2.2024
Date of Last Revision: 04/24

3

Concert Genetics Genetic Testing: Aortopathies and Connective Tissue Disorders
V2.2024
Date of Last Revision: 04/24

OTHER RELATED POLICIES

This policy document provides criteria for genetic testing for cardiovascular disorders. Please refer to:

• Genetic Testing: Cardiac Disorders for criteria related to arrhythmias and cardiomyopathies.
• Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay for criteria related to genetic disorders that affect multiple organ systems.
• Genetic Testing: Prenatal Diagnosis (via amniocentesis, CVS, or PUBS) and Pregnancy Loss for coverage related to prenatal and pregnancy loss diagnostic genetic testing.
• Genetic Testing: Preimplantation Genetic Testing for criteria related to genetic testing of embryos prior to in vitro fertilization.
• Genetic Testing: General Approach to Genetic and Molecular Testing for criteria related to aortopathies and connective tissue disorders not specifically discussed in this or another non-general policy.

back to top

4

Concert Genetics Genetic Testing: Aortopathies and Connective Tissue Disorders
V2.2024
Date of Last Revision: 04/24

CRITERIA

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:

CONNECTIVE TISSUE DISORDERS

*If a panel is performed, the appropriate panel code should be used

back to top

MARFAN SYNDROME

back to top

LOEYS-DIETZ SYNDROME

back to top

FAMILIAL THORACIC AORTIC ANEURYSM AND DISSECTION (TAAD)

Familial Thoracic Aortic Aneurysm and Dissection (TAAD) Multigene Panel

I. Familial thoracic aortic aneurysm and dissection (TAAD) multigene panel analysis (81405, 81406, 81408, 81410, 81411, 81479) to establish a genetic diagnosis for TAAD is considered *medically necessary** when:

A. The member/enrollee has aortic root enlargement or has had thoracic aneurysm or a type A or type B aortic dissection, AND  
B. The member/enrollee does not otherwise meet diagnostic criteria for another connective tissue disorder, AND

7

Concert Genetics Genetic Testing: Aortopathies and Connective Tissue Disorders
V2.2024
Date of Last Revision: 04/24

C. The member/enrollee has a family history of dilation or dissection of the aortic root, consistent with autosomal dominant inheritance.

II. Thoracic aortic aneurysm and dissection (TAAD) multigene panel analysis (81405, 81406, 81408, 81410, 81411, 81479) to establish a genetic diagnosis for TAAD is considered investigational for all other indications.

*If a panel is performed, the appropriate panel code should be used

back to top

EHLERS-DANLOS SYNDROME

back to top

Vascular Ehlers-Danlos Syndrome (vEDS)

back to top

OTHER COVERED CONNECTIVE TISSUE DISORDERS

The following is a list of conditions that have a known genetic association. Due to their relative rareness, it may be appropriate to cover these genetic tests to establish or confirm a diagnosis.

I. Genetic testing to establish or confirm one of the following connective tissue disorders (81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408) is considered medically necessary when the member/enrollee demonstrates clinical features* consistent with the disorder (the list is not meant to be comprehensive, see II below):

A. Arthrochalasia EDS (COL1A1, COL1A2)  
B. Brittle cornea syndrome (ZNF469, PRDM5)  
C. Cardiac-valvular EDS (COL1A2)  
D. Classical-like EDS (TNXB)  
E. Dermatosparaxis EDS (ADAMTS2)  
F. Kyphoscoliotic EDS (PLOD1, FKBP14)  
G. Musculocontractural EDS (CHST14, DSE)  
H. Myopathic EDS (COL12A1)  
I. Periodontal EDS (C1R, C1S)  
J. Spondylodysplastic EDS (B4GALT7, B3GALT6, SLC39A13)

II. Genetic testing to establish or confirm the diagnosis of all other connective tissue disorders (81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408) not specifically

10

Concert Genetics Genetic Testing: Aortopathies and Connective Tissue Disorders
V2.2024
Date of Last Revision: 04/24

CENTENE
Corporation

discussed within this or another medical policy will be evaluated by the criteria outlined in
General Approach to Genetic and Molecular Testing (see policy for Criteria).

*Clinical features for a specific disorder may be outlined in resources such as GeneReviews, OMIM, National Library
of Medicine, Genetics Home Reference, or other scholarly source.

back to top

DEFINITIONS

1. Close relatives include first, second, and third degree blood relatives:
   a. First-degree relatives are parents, siblings, and children
   b. Second-degree relatives are grandparents, aunts, uncles, nieces, nephews,
   grandchildren, and half siblings
   c. Third-degree relatives are great grandparents, great aunts, great uncles, great
   grandchildren, and first cousins

back to top

BACKGROUND AND RATIONALE

Comprehensive Connective Tissue Disorders Multigene Panel

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes
through a rigorous editing and peer review process before being published online.

GeneReviews: Classic Ehlers-Danlos Syndrome

The GeneReviews for Ehlers-Danlos Syndrome (EDS) states that “Molecular genetic testing
approaches can include concurrent (or serial) single-gene testing, use of a multigene panel, and
more comprehensive genomic testing. A multigene panel that includes COL5A1, COL5A2,
COL1A1, and other genes of interest may…be considered.”

GeneReviews: Hypermobile Ehlers-Danlos Syndrome

Per the Hypermobile Ehlers-Danlos Syndrome (EDS) GeneReviews, “if an individual’s personal
or family history is suggestive of one of the other types of EDS or another hereditary disorder of
connective tissue or arterial fragility syndrome, analysis of an associated gene or multigene
connective tissue disease panel may be appropriate.”

GeneReviews: FBN1-Related Marfan Syndrome

Per the FBN1-Related Marfan Syndrome Gene Reviews, “molecular genetic testing approaches
can include a combination of gene-targeted testing (single-gene testing, multigene panel) and
comprehensive genomic testing (exome sequencing, genome sequencing) depending on the
phenotype. A Marfan syndrome/Loeys-Dietz syndrome/familial thoracic aortic aneurysms and
dissections multigene panel that includes FBN1 and other genes of interest is most likely to
identify the genetic cause of the condition while limiting identification of variants of uncertain
significance and pathogenic variants in genes that do not explain the underlying phenotype.”

GeneReviews: Loeys-Dietz Syndrome

Per the Loeys-Dietz Syndrome (LDS) GeneReviews, “When the clinical findings suggest the
diagnosis of LDS, molecular genetic testing approaches can include serial single-gene testing or
use of a multigene panel. A multigene Marfan syndrome/Loeys-Dietz syndrome/familial
thoracic aortic aneurysms and dissections panel that includes SMAD2, SMAD3, TGFB2, TGFβ3,
TGFBR1, and TGFBR2 as well as a number of other genes associated with disorders that include
aortic aneurysms and dissections may be offered by clinical laboratories.”

Marfan Syndrome - FBN1 Sequencing and/or Deletion/Duplication Analysis

American College of Medical Genetics and Genomics (ACMG)

American College of Medical Genetics and Genomics (2012) issued guidelines on the evaluation
of adolescents or adults with some features of Marfan syndrome (MFS). Recommendations
included the following:

• If there is no family history of MFS, then the subject has the condition under any of the
  following four situations:
  
  • A dilated aortic root (defined as greater than or equal to two standard deviations
    above the mean for age, sex, and body surface area) and ectopia lentis
  • A dilated aortic root and a mutation [pathogenic variant] in FBN1 that is clearly
    pathologic
  • A dilated aortic root and multiple systemic features
  • Ectopia lentis and a mutation [pathogenic variant] in FBN1 that has previously
    been associated with aortic disease.

• If there is a positive family history of MFS (independently ascertained with these
  criteria), then the subject has the condition under any of the following three situations:
  
  • Ectopia lentis
  • Multiple systemic features or
  • A dilated aortic root (if over 20 years, greater than two standard deviations; if
    younger than 20, greater than three standard deviations)

GeneReviews: FBN1-Related Marfan Syndrome

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes
through a rigorous editing and peer review process before being published online.

Marfan syndrome should be suspected in individuals with the following clinical findings and
family history:

• Aortic root enlargement (Z-score ≥2.0). Note: Aortic size must be standardized to age
  and body size for accurate interpretation. A Z-score ≥2.0 indicates a value at or above the
  95th percentile, while a Z-score ≥3.0 indicates a value at or above the 99th percentile.
  References and calculators for this determination are available at the Marfan Foundation
  website.
• Ectopia lentis; most reliably diagnosed by slit-lamp examination after maximal pupillary
  dilation
• A systemic score ≥7

Additionally, GeneReviews states the diagnosis of Marfan syndrome is established in a proband
(by definition a person without a known family history of Marfan syndrome) who has an FBN1
pathogenic variant known to be associated with Marfan syndrome and EITHER of the following
[Loeys et al 2010]:

• Aortic root enlargement (Z-score >2.0)
• Ectopia lentis

Loeys-Dietz Syndrome Multigene Panel

American College of Medical Genetics and Genomics (ACMG)

American College of Medical Genetics and Genomics (2012) issued guidelines on the evaluation
of adolescents or adults with some features of Marfan syndrome (MFS) (including Loeys-Dietz
syndrome), which recommendations included the following:

Genetic testing for Loeys-Dietz Syndrome (LDS) can aid in the diagnosis of LDS in addition to
physical exam, echocardiography, dilated eye exam and MRI of the head, neck, thorax, abdomen
and pelvis. Features of LDS include characteristic facial features, craniosynostosis, bifid uvula or
cleft palate, tortuosity of the aorta and its branches, aortic dilatation and dissection, and joint
hypermobility.

Patients have had mutations in one or another of the receptors for TGFβ. In a patient found to
have consistent facial features, bifid uvula, and arterial tortuosity, the diagnosis can be confirmed
with molecular testing. Tortuosity can sometimes be isolated (e.g., found only in the head and
neck). (p. 175)

MacCarrick et al; 2014

MacCarrick et al (2014) proposed a nosology in which a mutation in TGFBR1, TGFBR2,
SMAD3 or TGFB2 in combination with documented aneurysm or dissection should be sufficient
for the diagnosis of LDS. (p. 576)

GeneReviews: Loeys-Dietz Syndrome

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes
through a rigorous editing and peer review process before being published online. The
GeneReviews for Loeys-Dietz syndrome (Loeys and Dietz, 2018) indicates the diagnosis of
Loeys-Dietz syndrome is established in a proband (by definition a person without a known
family history of LDS) who has a heterozygous pathogenic (or likely pathogenic) variant in
SMAD2, SMAD3, TGFB2, TGFβ3, TGFBR1, or TGFBR2 and EITHER of the following: (p. 4)

• Aortic root enlargement (defined as an aortic root z-score ≥2.0) or type A dissection
• Compatible systemic features including characteristic craniofacial, skeletal, cutaneous,
  and/or vascular manifestations found in combination. Special emphasis is given to arterial
  tortuosity, prominently including the head and neck vessels, and to aneurysms or
  dissections involving medium-to-large muscular arteries throughout the arterial tree.

Familial Thoracic Aortic Aneurysm and Dissection (TAAD) Multigene Panel

American College of Medical Genetics and Genomics (ACMG)

American College of Medical Genetics and Genomics (2012) issued guidelines on the evaluation
of adolescents or adults with some features of Marfan syndrome (MFS) (including TAAD),
which recommendations included the following (pages 174-175):

Genetic testing for TAAD can aid in the diagnosis in addition to physical exam, family history,
dilated eye exam, echocardiography and vasculature imaging. Diagnostic criteria for TAAD
include autosomal dominant history of dilation or dissection of the aortic root, ascending aorta
or descending aorta in the absence of major criteria for the diagnosis of Marfan syndrome or
other connective tissue disease.

American Heart Association/American College of Cardiology

The ACC and AHA published a joint guideline (2022) in which genetic testing is recommended
for patients with aortic root/ascending aortic aneurysms or aortic dissection and risk factors for
heritable thoracic aortic disease (strong recommendation, moderate quality of evidence). These
risk factors include:

• Thoracic aortic disease (TAD) and syndromic features of Marfan, Loeys-Dietz or
  vascular Ehlers-Danlos syndrome
• TAD presentation under 60
• Family history of either TAD or peripheral/intracranial aneurysms in first or second
  degree relative
• History of unexplained sudden death at a relatively young age in first or second degree
  relative. (p. e361)
• A multigene panel comprising all genes suspected to cause HTAD is the most cost-
  effective and clinically useful approach to testing. (p. e362)

GeneReviews: Heritable Thoracic Aortic Disease Overview

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes
through a rigorous editing and peer review process before being published online.

Per the Heritable Thoracic Disease GeneReviews article, “A multigene panel that includes
genes associated with HTAD [heritable thoracic aortic disease] is recommended.” Per Table 1 of
this article, these genes include: ACTA2, COL3A, FBN1, MYH11, MYLK, SMAD3, TGFB2,
TGFBR1, TGFBR2, LOX, PRKG1, EFEMP2, FOXE3, MFAP5, SMAD2, BGN, CBS, COL4A5,
ELN, FBN2, FLNA, HCN4, NOTCH1, MAT2A, PKD1, PKD2, SKI, SLC2A10, SMAD4, TGFB3.

EHLERS-DANLOS SYNDROME

Classic Ehlers-Danlos Syndrome (cEDS) Multigene Panel

International EDS Consortium

The 2017 International Classification of the Ehlers-Danlos Syndromes (p. 11 and 13) included
the following clinical features for the associated conditions. Confirmatory molecular testing is
needed to reach a final diagnosis.

Classical EDS (cEDS):

• Major criteria
  
  1. Skin hyperextensibility and atrophic scarring
  2. Generalized joint hypermobility (GJH)
• Minor criteria
  
  1. Easy bruising
  2. Soft, doughy skin
  3. Skin fragility (or traumatic splitting)
  4. Molluscoid pseudotumors
  5. Subcutaneous spheroids
  6. Hernia (or history thereof)
  7. Epicanthal folds
  8. Complications of joint hypermobility (e.g., sprains, luxation/subluxation, pain,
     flexible flatfoot)
  9. Family history of a first degree relative who meets clinical criteria

Minimal Criteria suggestive for cEDS:

• Major criterion (1): skin hyperextensibility and atrophic scarring
  
  • Plus
  • Either major criterion (2): GJH
  • And/or at least three minor criteria

More than 90% of cEDS patients harbor a heterozygous mutation in one of the genes
encoding type V collagen (COL5A1 and COL5A2). (p. 13)

GeneReviews: Classic Ehlers-Danlos Syndrome

GeneReviews is an expert-authored review of current literature on a genetic disease, and goes
through a rigorous editing and peer review process before being published online.

The GeneReviews for Ehlers-Danlos Syndrome (EDS) states that “Molecular genetic testing
approaches can include concurrent (or serial) single-gene testing, use of a multigene panel, and
more comprehensive genomic testing. A multigene panel that includes COL5A1, COL5A2… and
other genes of interest may…be considered.”

Vascular Ehlers-Danlos Syndrome (vEDS) - COL3A1 Sequencing and/or

Deletion/Duplication Analysis

The 2017 International Classification of the Ehlers-Danlos Syndromes (Malfait et al, 2017, p. 16)
included the following clinical features for the associated conditions:

Vascular EDS (vEDS)

• Major criteria
  
  1. Family history of vEDS with documented causative variant in COL3A1
  2. Arterial rupture at a young age
  3. Spontaneous sigmoid colon perforation in the absence of known diverticular
     disease or other bowel pathology
  4. Uterine rupture during the third trimester in the absence of previous C-section
     and/or severe peripartum perineum tears
  5. Carotid-cavernous sinus fistula (CCSF) Formation in the absence of trauma
• Minor criteria
  
  1. Bruising unrelated to identified trauma and/or in unusual sites such as cheeks and
     back
  2. Thin, translucent skin with increased venous visibility
  3. Characteristic facial appearance
  4. Spontaneous pneumothorax
  5. Acrogeria
  6. Talipes equinovarus
  7. Congenital hip dislocation
  8. Hypermobility of small joints
  9. Tendon and muscle rupture
  10. Keratoconus
  11. Gingival recession and gingival fragility
  12. Early onset varicose veins (under age 30 and nulliparous in those with a female
      reproductive system)

Minimal criteria suggestive for vEDS:

A family history of the disorder, arterial rupture or dissection in individuals less
than 40 years of age, unexplained sigmoid colon rupture, or spontaneous
pneumothorax in the presence of other features consistent with vEDS should all
lead to diagnostic studies to determine if the individual has vEDS. Testing for
vEDS should also be considered in the presence of a combination of the other
“minor” clinical features listed above. Even for experienced clinicians the clinical
diagnosis of vEDS may be difficult. Because of implications for treatment, natural
history, and recurrence risk, the diagnosis of vEDS rests on the identification of a
causative variant in one allele of COL3A1.

Patients with vEDS typically harbor a heterozygous variant in the COL3A1 gene,
encoding type III collagen, with the rare exception of specific heterozygous
variants in COL1A1. Verification of clinical diagnosis via Molecular screening by
Sanger sequencing of COL3A1, or targeted resequencing of a gene panel that
includes COL3A1 and COL1A1 is indicated. When no variant is identified, this
approach should be complemented with a CNV detection strategy to identify large
deletions or duplications.

back to top

Reviews, Revisions, and Approvals

Reviews, Revisions, and Approvals

back to top

Important Reminder

This clinical policy has been developed by appropriately experienced and licensed health care
professionals based on a review and consideration of currently available generally accepted
standards of medical practice; peer-reviewed medical literature; government agency/program
approval status; evidence-based guidelines and positions of leading national health professional
organizations; views of physicians practicing in relevant clinical areas affected by this clinical
policy; and other available clinical information. The Health Plan makes no representations and
accepts no liability with respect to the content of any external information used or relied upon in
developing this clinical policy. This clinical policy is consistent with standards of medical
practice current at the time that this clinical policy was approved. “Health Plan” means a health
plan that has adopted this clinical policy and that is operated or administered, in whole or in part,
by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.

Concert Genetics Genetic Testing: Aortopathies and Connective Tissue Disorders
V2.2024
Date of Last Revision: 04/24

CENTENE Corporation

22