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Coding Implications

# CONCERT GENETICS GENETIC
# TESTING: SKELETAL DYSPLASIA
# AND RARE BONE DISORDERS

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

## OVERVIEW

Skeletal dysplasias are a category of rare genetic disorders that affect bones and joints and are
estimated to affect 2.4 per 10,000 births, and some forms of skeletal dysplasia can be suspected
based on prenatal ultrasound. There are more than 350 distinct skeletal disorders that have been
described, and some skeletal dysplasias can be lethal, often due to a significantly small rib cage
that restricts lung development. The osteogenesis imperfecta group of disorders are sometimes
classified as skeletal dysplasias, while other times they are considered bone fragility disorders.

Genetic testing has allowed for gene identification in more than two thirds of the skeletal
dysplasias. Testing allows for more precise diagnosis facilitating health care providers’ care
based on the established natural history of the individual disorder. For some skeletal dysplasias,
knowing the specific disease causing variant or variants can impart prognostic information. A
few skeletal dysplasias are currently amenable to pharmacologic therapy, though such therapies
may be reserved for patients with confirmed genetic diagnosis. The familial recurrence risk and
long term natural history differs based on the underlying genetic basis of disease.

Per GeneReviews*, Osteogenesis Imperfecta (OI) should be distinguished from child physical
abuse/non-accidental trauma (NAT). The prevalence of physical abuse is much greater than the
prevalence of OI, and on rare occasions, the two can be present concurrently. Patient history,
family history, physical examination, radiographic imaging, fracture investigation, and the
clinical course all contribute to distinguishing OI from NAT. The overlap in clinical features
includes multiple or recurrent fractures, fractures that do not match the history of trauma, and the
finding of fractures of varying ages and at different stages of healing. Rib fractures are much
more common in NAT than in osteogenesis imperfecta³.

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Concert Genetics Genetic Testing: Skeletal Dysplasia and Rare Bone
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*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.

# 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
2023, 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.

| Criteria Sections | Example Tests (Labs) | Common CPT Codes | Common ICD Codes | Ref |
|-------------------|---------------------|-----------------|-----------------|-----|
| Osteogenesis Imperfecta | Osteogenesis imperfecta COL1A1 & COL1A2 NGS Panel (Connective Tissue Gene Tests) | 81406, 81408, 81479 | Q78.0, Z82.79 | 3 |
|                   | Osteogenesis Imperfecta Panel (PreventionGenetics, part of Exact Sciences) |                 |                 |     |
|                   | Osteogenesis Imperfecta NGS Panel - Dominant & Recessive Next Generation Sequencing (Connective Tissue Gene Tests) |                 |                 |     |
|                   | Skeletal Disorders Panel (Invitae) |                 | M85, Q77, Q78 | 1, 7, 8 |

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Concert Genetics Genetic Testing: Skeletal Dysplasia and Rare Bone
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| Multigene Panel Analysis for Skeletal Dysplasia or Rare Bone Disorder | Skeletal Dysplasia Core & Extended NGS Panel (Connective Tissue Gene Tests) | 81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479 |                 |     |
|                                                                 | Comprehensive Skeletal Dysplasias and Disorders Panel (Blueprint Genetics) | 81236, 81404, 81406, 81408, 81479 |                 |     |
| **Other Covered Skeletal Dysplasias and Rare Bone Disorders** | varies | 81400, 81401, 81402, 81403, 81404, 81405, 81406, 81407, 81408, 81479 | M85, Q77, Q78 | 2, 4, 5, 6 |

## OTHER RELATED POLICIES

This policy document provides criteria for Genetic Testing for Skeletal Dysplasia and Rare Bone
Disorders. Please refer to:

- **Genetic Testing: Aortopathies and Connective Tissue Disorders** for criteria related to
  Ehlers-Danlos syndrome and other connective tissue disorders.
- **Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and
  Developmental Delay** for criteria related to diagnostic testing for disorders that affect
  multiple systems.
- **Genetic Testing: General Approach to Genetic and Molecular Testing** for criteria related
  to skeletal dysplasias and rare bone disorders that is not specifically discussed in this or
  another non-general policy.

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Concert Genetics Genetic Testing: Skeletal Dysplasia and Rare Bone
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# 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:



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Concert Genetics Genetic Testing: Skeletal Dysplasia and Rare Bone
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Concert Genetics Genetic Testing: Skeletal Dysplasia and Rare Bone
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*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.

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## DEFINITIONS

1. Non-accidental Trauma (NAT) refers to injury that is purposely inflicted upon a child
(e.g., child abuse). NAT often occurs as injury to the skin and soft tissue, but
approximately a third of NATs are fractures.

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# BACKGROUND AND RATIONALE

## Osteogenesis Imperfecta

### GeneReviews: COL1A1/2 Osteogenesis Imperfecta

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 recommended diagnostic testing for osteogenesis imperfecta is as follows:

COL1A1/2 osteogenesis imperfecta (OI) should be suspected in individuals with the following
clinical, radiographic, and laboratory features.

- Fractures with minimal or no trauma in the absence of other factors, such as non-
  accidental trauma (NAT) or other known disorders of bone

- Short stature or stature shorter than predicted based on stature of unaffected family
  members, often with bone deformity

- Blue/gray scleral hue

- Dentinogenesis imperfecta (DI)

- Progressive, postpubertal hearing loss

- Ligamentous laxity and other signs of connective tissue abnormality

- Family history of OI, usually consistent with autosomal dominant inheritance

Radiographic features of OI change with age. The major findings include the following:

- Fractures of varying ages and stages of healing, often of the long bones but may also
  rarely involve ribs and skull. Metaphyseal fractures can be seen in a very small number of
  children with OI. Rib fractures are much more common in NAT than in OI.

- “Codfish” vertebrae, which are the consequence of spinal compression fractures, seen
  more commonly in adults.

- Wormian bones, defined as “sutural bones which are 6 mm by 4 mm (in diameter) or
  larger, in excess of ten in number, with a tendency to arrange in a mosaic pattern.”
  Wormian bones are suggestive of but not pathognomonic for OI.

- Protrusio acetabuli, in which the socket of the hip joint is too deep and the acetabulum
  bulges into the cavity of the pelvis causing intrapelvic protrusion of the acetabulum.

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Concert Genetics Genetic Testing: Skeletal Dysplasia and Rare Bone
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- Low bone mass or osteoporosis detected by dual energy x-ray absorptiometry (DEXA).
  Bone density can be normal, especially in individuals with OI type I, as DEXA measures
  mineral content rather than collagen.

### Laboratory features

- Serum concentrations of vitamin D, calcium, phosphorous, and alkaline phosphatase are
  typically normal; however, alkaline phosphatase may be elevated acutely in response to
  fracture and rare instances of abnormally low alkaline phosphatase levels have been
  noted anecdotally in severe OI.

- Analysis of type 1 collagen synthesized in vitro by culturing dermal fibroblasts obtained
  from a small skin biopsy reflects the structure and quantity of the collagen. The
  sensitivity of biochemical testing is approximately 90% in individuals with clinically
  confirmed OI. Biochemical analysis is essentially no longer used clinically with the
  advances in molecular diagnostics.

“A multigene panel that includes COL1A1, COL1A2, and other genes of interest is most likely to
identify the genetic cause of the condition at the most reasonable cost while limiting
identification of variants of uncertain significance and variants in genes that do not explain the
underlying phenotype.”

### Multigene Panel Analysis for Skeletal Dysplasia or Rare Bone Disorder

*Krakow et al 2009*

A guideline for prenatal diagnosis of fetal skeletal dysplasias (Krakow, Lachman, Rimoin, 2009)
recommends the follow criteria:

- Fetuses with long bone measurements at or less than the 5th centile or greater than 3 SD
  below the mean should be evaluated in a center with expertise in the recognition of
  skeletal dysplasias. If the patient cannot travel, arrangements may be able to be made for
  evaluation of ultrasound videotapes or hard copy images.

- The following fetal ultrasound measurements should be visualized and plotted against
  normative values: fetal cranium (biparietal diameter and head circumference), facial
  profile, mandible, clavicle, scapula, chest circumference, vertebral bodies, all fetal long
  bones, and the hands and feet. Fetuses with long bone parameters more than 3 SD below
  the mean should be strongly suspected of having a skeletal dysplasia, especially if the
  head circumference is greater than the 75th centile

- Lethality should be determined by chest circumference to abdominal circumference ratio
  and/or femur length to abdominal circumference measurement ratio. A chest-to

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abdominal circumference ratio of less than 0.6 or femur length to abdominal
circumference ratio of 0.16 strongly suggests a perinatal lethal disorder, although there
are exceptions. The findings should be conveyed to the physicians caring for the patient
and to the patient. (p. 5)

In addition, close attention should be paid to the shape and mineralization pattern of the fetal
calvarium and fetal skeleton (poor or ectopic mineralization). Determining the elements of the
skeleton that are abnormal, coupled with the findings of mineralization and shape of the bones
can aid in diagnosis. (p. 3)

### American College of Medical Genetics and Genomics (ACMG)

For diagnosis of genetic causes of short stature, the American College of Medical Genetics
practice guideline for evaluation of short stature (Seaver et al, 2009) is as follows:

The definition most commonly used for short stature is height-for-age less than two
standard deviations below average for gender, which is demonstrated on the standard
growth curves as a length or height less than the 3rd centile. (p. 466)

### Nikkel 2017

Nikkel (2017) indicated the value of multigene panels for skeletal dysplasias with the following:

- The use of multigene panels, using next generation sequence technology, has improved
  our ability to quickly identify the genetic etiology, which can impact management. (p.
  419)

- One should ensure that a panel contains all the genes under consideration and there is
  appropriate deletion/duplication analysis when such pathogenic changes are noted to
  occur in the gene. (p. 420-421)

- A patient may present with a non-specific dysplasia or be too young for some of the
  cardinal features to be present on radiographs. There may also be significant prognostic
  implications regarding survival dependent upon the diagnosis, thus an urgency to get this
  information. In these instances, a skeletal dysplasia gene panel can greatly reduce the
  time to diagnosis and can be more cost- and time-efficient rather than testing gene by
  gene. (p. 420)

### Other Covered Skeletal Dysplasia and Rare Bone Disorders

*International Skeletal Dysplasia Society*

Concert Genetics Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders

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The International Skeletal Dysplasia Society published an updated categorization of skeletal dysplasias (Mortier, 2019).

This newest and tenth version of the Nosology comprises 461 different diseases that are classified into 42 groups based on their clinical, radiographic, and/or molecular phenotypes. Remarkably, pathogenic variants affecting 437 different genes have been found in 425/461 (92%) of these disorders. By providing a reference list of recognized entities and their causal genes, the Nosology should help clinicians achieve accurate diagnoses for their patients and help scientists advance research in skeletal biology. (p. 2393)

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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.

The purpose of this clinical policy is to provide a guide to medical necessity, which is a component of the guidelines used to assist in making coverage decisions and administering benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions, and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy,

Concert Genetics Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders

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contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures.

This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. The Health Plan retains the right to change, amend or withdraw this clinical policy, and additional clinical policies may be developed and adopted as needed, at any time.

This clinical policy does not constitute medical advice, medical treatment, or medical care. It is not intended to dictate to providers how to practice medicine. Providers are expected to exercise professional medical judgment in providing the most appropriate care and are solely responsible for the medical advice and treatment of member/enrollees. This clinical policy is not intended to recommend treatment for member/enrollees. Member/enrollees should consult with their treating physician in connection with diagnosis and treatment decisions.

Providers referred to in this clinical policy are independent contractors who exercise independent judgment and over whom the Health Plan has no control or right of control. Providers are not agents or employees of the Health Plan.

This clinical policy is the property of the Health Plan. Unauthorized copying, use, and distribution of this clinical policy or any information contained herein are strictly prohibited. Providers, member/enrollees, and their representatives are bound to the terms and conditions expressed herein through the terms of their contracts. Where no such contract exists, providers, member/enrollees and their representatives agree to be bound by such terms and conditions by providing services to member/enrollees and/or submitting claims for payment for such services.

Note: For Medicaid member/enrollees, when state Medicaid coverage provisions conflict with the coverage provisions in this clinical policy, state Medicaid coverage provisions take precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to this clinical policy.

Note: For Medicare member/enrollees, to ensure consistency with the Medicare National Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable NCDs and LCDs and Medicare Coverage Articles should be reviewed prior to applying the criteria set forth in this clinical policy. Refer to the CMS website at http://www.cms.gov for additional information.

Concert Genetics Genetic Testing: Skeletal Dysplasia and Rare Bone Disorders

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Date of Last Revision: 04/24

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