Genetic Testing for Adolescent Idiopathic Scoliosis AHS – G2036

Description of Procedure or Service

Scoliosis is a disorder with abnormal rotation and curvature of the spine. In most causes the cause is idiopathic. Adolescent Idiopathic Scoliosis (AIS) typically occurs after the age of 10, and the disease tends to run in families. Most individuals with scoliosis do not suffer from progression of the curvature, and treatment is needed only for a small percentage of patients (Scherl, 2018).

Genetic markers have been identified related to adolescent idiopathic scoliosis. The ScoliScore™ Test is the first clinically validated genetic test for adolescent idiopathic scoliosis.

***Note: This Medical Policy is complex and technical. For questions concerning the technical language and/or specific clinical indications for its use, please consult your physician. 

Policy

Genetic testing for adolescent idiopathic scoliosis is considered investigational. BCBSNC does not provide coverage for investigational services or procedures.

Benefits Application

This medical policy relates only to the services or supplies described herein. Please refer to the Member's Benefit Booklet for availability of benefits. Member's benefits may vary according to benefit design; therefore member benefit language should be reviewed before applying the terms of this medical policy. 

When genetic testing for Adolescent Idiopathic Scoliosis is covered

Not applicable

When genetic testing for Adolescent Idiopathic Scoliosis is not covered

DNA based prognostic testing for adolescent idiopathic scoliosis is considered investigational. BCBSNC does not cover investigational services or procedures

Policy Guidelines

Literature review

Adolescent Idiopathic Scoliosis is the most common spinal deformity, affecting between 2-3% of children in the United States (Grauers, Einarsdottir, & Gerdhem, 2016). However, only 10% of adolescents with AIS progress to more severe curvature requiring treatment (Gore, Passehl, Sepic,& Dalton, 1981). Although males and females are affected equally, females are significantly more likely to have curve progression (Miller, 1999).

The etiology of AIS is uncertain, but a genetic contribution is suggested by familial inheritance (Simony, Carreon, Hjmark, Kyvik, & Andersen, 2016). Increased levels of calmodulin in platelets and an asymmetrical distribution of calmodulin in paraspinal muscles(Acaroglu, Akel, Alanay, Yazici, & Marcucio, 2009) , uncoordinated growth of the vertebral bodies in relation to the dorsal elements(Guo, Chau, Chan, & Cheng, 2003), higher growth velocity during puberty (Cheung et al., 2006), and high levels of cartilage oligomeric matrix protein (Gerdhem et al., 2015), have all been investigated.

Several genetic candidates have also been identified. Takahashi et al (2011)performed a large GWAS which found an association with a variant downstream of LBX1. Kou et al (2013)identified GPR126 mutation in a large Japanese GWAS. GPR126 was found to be highly expressed in cartilage and cause delayed ossification in zebrafish. Bashal et al (2014) completed exome sequencing for three members of a multigenerational family with idiopathic scoliosis, resulting in the identification of a variant in the HSPG2 gene as a potential contributor to the phenotype. Buchan et al (2014) used genome-wide rare variant burden analysis using exome sequence data, to identify fibrillin-1 (FBN1) as the most significantly associated gene with AIS, and scoliosis severity, suggesting that rare variants may be useful as predictors of curve progression. Ogura et al (2015) identified a variant of BNC2, overexpression of which resulted in body curvature in zebrafish in a dose dependent manner. Haller et al (2016) analyzed exome sequence data of 391 severe AIS cases and 843 controls of European ancestry using a pathway burden analysis which indicated a complex genetic architecture of AIS in which a polygenic burden of rare variants across extracellular matrix genes contributes strongly to risk.

Clinical Validity and Utility

Determination of which curves will progress is difficult. Prognostic testing for AIS has the potential to reduce psychological trauma, serial exposure to diagnostic radiation, unnecessary treatments, and direct and indirect costs-of-care related to scoliosis monitoring in low-risk patients. Ward et al (2010) used logistic regression to develop and validate an algorithm to predict spinal curve progression incorporating genotypes for 53 single nucleotide polymorphisms and the patient's presenting spinal curve, marketed as Scoliscore. Although initial results were significant, the association of these variants to progression of scoliosis has not been replicated in either a Japanese or a French-Canadian cohort(Ogura et al., 2013; Tang et al., 2015).

The replication association study by Tang et al (2015) to determine whether the 53 single nucleotide polymorphisms (SNPs) that were previously associated with spinal deformity progression in an American Caucasian cohort are similarly associated in French-Canadian population found that none of the SNPs used in ScoliScore were associated with adolescent idiopathic scoliosis curve progression or curve occurrence in French-Canadian population.

Roye et al (2012) compared the risk stratification between ScoliScore and traditional clinical estimates to determine whether ScoliScore provides unique information. The study showed that clinical assessment classified more patients as high-risk (47 versus 9 percent) and AIS-PT categorized more patients as low risk (36 versus 2 percent). The authors concluded that ScoliScore provides unique information to traditional clinical predictors of curve progression.

Roye et al (2015) conducted a dual-center retrospective cohort study of 126 Caucasian patients with AIS and Cobb angle between 10 and 25° to determine if the ScoliScore effectively predicted the risk of curve progression in patients with mild and moderate adolescent idiopathic scoliosis. The study concluded that ScoliScores did not differ between patients with and without curve progression, and the negative and positive predictive values were lower in the study than in the previously published validation study by the developers of the test.

Scherl (2018) stated that genetic testing for prognosis of adolescent idiopathic scoliosis (i.e., the AIS prognostic test [AIS-PT], marketed as ScoliScore) is not recommended. The author concluded that “lack of validation of the AIS-PT in independent cohorts may be related to differences in the test population, genetic variability, or loss to follow-up of patients with non-progressive scoliosis. Until these issues are resolved, we continue to use clinical predictors rather than the AIS-PT to predict the risk for progression in patients with AIS”.

Applicable Federal Regulations

The ScoliScore™ AIS (adolescent idiopathic scoliosis) prognostic DNA-based test (Axial Biotech, Salt Lake City, Utah) is considered a laboratory developed test (LDT); developed, validated and performed by individual laboratories.

LDTs are regulated by the Centers for Medicare and Medicaid (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA’88).

As an LDT, the U. S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use.

Guidelines and Recommendations

Practice Guidelines and Position Statements International Scientific Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT)

SOSORT released revised evidence-based guidelines on conservative treatment of idiopathic scoliosis (Negrini et al., 2018) align the guidelines with the new scientific evidence to assure faster knowledge transfer into clinical practice. They found that “Recently developed genetic assessment, with 53 identified loci, can now help predict the risk of IS progression. The determination of the polymorphism of selected genes is meant to facilitate the assignment of a patient to a progressive or stable group. Unfortunately, the data originating from one population often are not confirmed in replication studies involving other populations. A prognostic genetic test, known as ScoliScore, has also been developed. Although these initial results have been promising, their generalizability is still uncertain.”

School screening programs are recommended for the early diagnosis of idiopathic scoliosis using the Scoliometer during trunk forward bend (Adam’s test) and s 5° and 7° of angle of trunk rotation should be used as criteria for referral.

Screening is also recommended every time they evaluate children aged from 8 to 15 years, pediatricians, general practitioners and sports physicians perform the Adam’s test for scoliosis screening purposes, using the Scoliometer.

U.S. Preventive Services Task Force (USPSTF)

The USPSTF issued an updated recommendation (Grossman et al., 2018)that the current evidence is insufficient to assess the balance of benefits and harms of screening for adolescent idiopathic scoliosis in children and adolescents aged 10 to 18 years. No USPSTF recommendations for DNAbased testing for AIS were identified.

American Academy of Family Physicians (AAFP)

The AAFP published a clinical preventative service recommendation (2018) which states that “The AAFP supports the U.S. Preventive Services Task Force (USPSTF) clinical preventive service recommendation on this topic.”

The Scoliosis Research Society (SRS), American Academy of Orthopaedic Surgeons (AAOS), Pediatric Orthopaedic Society of North America (POSNA), and American Academy of Pediatrics (AAP)

The AAOS, SRS, POSNA, and AAP issued a statement (Hresko, Talwalkar, & Schwend, 2016) which states:

“The AAOS, SRS, POSNA, and AAP believe that there are documented benefits of earlier detection and non-operative management of AIS, earlier identification of severe deformities that are surgically treated, and incorporation of screening of children for AIS by knowledgeable health care providers as a part of their care.”

“AAOS, SRS, POSNA, and AAP believe that screening examinations for spine deformity should be part of the medical home preventive services visit for females at age 10 and 12 years, and males once at age 13 or 14 years.” 

Billing/Coding/Physician Documentation Information

This policy may apply to the following codes. Inclusion of a code in this section does not guarantee that it will be reimbursed. For further information on reimbursement guidelines, please see Administrative Policies on the Blue Cross Blue Shield of North Carolina web site at www.bcbsnc.com. They are listed in the Category Search on the Medical Policy search page.

Scientific Background and Reference Sources

AAFP. (2018). Scoliosis - Clinical Preventive Service Recommendation. from @aafp

Acaroglu, E., Akel, I., Alanay, A., Yazici, M., & Marcucio, R. (2009). Comparison of the melatonin and calmodulin in paravertebral muscle and platelets of patients with or without adolescent idiopathic scoliosis. Spine (Phila Pa 1976), 34(18), E659-663. doi:10.1097/BRS.0b013e3181a3c7a2

Baschal, E. E., Wethey, C. I., Swindle, K., Baschal, R. M., Gowan, K., Tang, N. L., . . . Miller, N. H. (2014). Exome sequencing identifies a rare HSPG2 variant associated with familial idiopathic scoliosis. G3 (Bethesda), 5(2), 167-174. doi:10.1534/g3.114.015669

Buchan, J. G., Alvarado, D. M., Haller, G. E., Cruchaga, C., Harms, M. B., Zhang, T., . . . Gurnett, C. A. (2014). Rare variants in FBN1 and FBN2 are associated with severe adolescent idiopathic scoliosis. Hum Mol Genet, 23(19), 5271-5282. doi:10.1093/hmg/ddu224

Cheung, C. S., Lee, W. T., Tse, Y. K., Lee, K. M., Guo, X., Qin, L., & Cheng, J. C. (2006). Generalized osteopenia in adolescent idiopathic scoliosis--association with abnormal pubertal growth, bone turnover, and calcium intake? Spine (Phila Pa 1976), 31(3), 330-338. doi:10.1097/01.brs.0000197410.92525.10

Gerdhem, P., Topalis, C., Grauers, A., Stubendorff, J., Ohlin, A., & Karlsson, K. M. (2015). Serum level of cartilage oligomeric matrix protein is lower in children with idiopathic scoliosis than in non-scoliotic controls. Eur Spine J, 24(2), 256-261. doi:10.1007/s00586-014-3691-2

Gore, D. R., Passehl, R., Sepic, S., & Dalton, A. (1981). Scoliosis screening: results of a community project. Pediatrics, 67(2), 196-200.

Grauers, A., Einarsdottir, E., & Gerdhem, P. (2016). Genetics and pathogenesis of idiopathic scoliosis. Scoliosis Spinal Disord, 11, 45. doi:10.1186/s13013-016-0105-8

Grossman, D. C., Curry, S. J., Owens, D. K., Barry, M. J., Davidson, K. W., Doubeni, C. A., . . . Tseng, C. W. (2018). Screening for Adolescent Idiopathic Scoliosis: US Preventive Services Task Force Recommendation Statement. Jama, 319(2), 165-172. doi:10.1001/jama.2017.19342

Guo, X., Chau, W. W., Chan, Y. L., & Cheng, J. C. (2003). Relative anterior spinal overgrowth in adolescent idiopathic scoliosis. Results of disproportionate endochondral-membranous bone growth. J Bone Joint Surg Br, 85(7), 1026-1031.

Haller, G., Alvarado, D., McCall, K., Yang, P., Cruchaga, C., Harms, M., . . . Gurnett, C. A. (2016). A polygenic burden of rare variants across extracellular matrix genes among individuals with adolescent idiopathic scoliosis. Hum Mol Genet, 25(1), 202-209. doi:10.1093/hmg/ddv463

Hresko, M. T., Talwalkar, V., & Schwend, R. (2016). Early Detection of Idiopathic Scoliosis in Adolescents. J Bone Joint Surg Am, 98(16), e67. doi:10.2106/jbjs.16.00224

Kou, I., Takahashi, Y., Johnson, T. A., Takahashi, A., Guo, L., Dai, J., . . . Ikegawa, S. (2013). Genetic variants in GPR126 are associated with adolescent idiopathic scoliosis. Nat Genet, 45(6), 676-679. doi:10.1038/ng.2639

Miller, N. H. (1999). Cause and natural history of adolescent idiopathic scoliosis. Orthop Clin North Am, 30(3), 343-352, vii.

Negrini, S., Donzelli, S., Aulisa, A. G., Czaprowski, D., Schreiber, S., de Mauroy, J. C., . . . Zaina, F. (2018). 2016 SOSORT guidelines: orthopaedic and rehabilitation treatment of idiopathic scoliosis during growth. Scoliosis Spinal Disord, 13, 3. doi:10.1186/s13013-017-0145-8

Ogura, Y., Kou, I., Miura, S., Takahashi, A., Xu, L., Takeda, K., . . . Ikegawa, S. (2015). A Functional SNP in BNC2 Is Associated with Adolescent Idiopathic Scoliosis. Am J Hum Genet, 97(2), 337-342. doi:10.1016/j.ajhg.2015.06.012

Ogura, Y., Takahashi, Y., Kou, I., Nakajima, M., Kono, K., Kawakami, N., . . . Ikegawa, S. (2013). A replication study for association of 53 single nucleotide polymorphisms in a scoliosis prognostic test with progression of adolescent idiopathic scoliosis in Japanese. Spine (Phila Pa 1976), 38(16), 1375-1379. doi:10.1097/BRS.0b013e3182947d21

Roye, B. D., Wright, M. L., Matsumoto, H., Yorgova, P., McCalla, D., Hyman, J. E., . . . Vitale, M. G. (2015). An Independent Evaluation of the Validity of a DNA-Based Prognostic Test for Adolescent Idiopathic Scoliosis. J Bone Joint Surg Am, 97(24), 1994-1998. doi:10.2106/jbjs.o.00217

Roye, B. D., Wright, M. L., Williams, B. A., Matsumoto, H., Corona, J., Hyman, J. E., . . . Vitale, M. G. (2012). Does ScoliScore provide more information than traditional clinical estimates of curve progression? Spine (Phila Pa 1976), 37(25), 2099-2103. doi:10.1097/BRS.0b013e31825eb605

Scherl, S. (2018). Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis - UpToDate. 

Simony, A., Carreon, L. Y., Hjmark, K., Kyvik, K. O., & Andersen, M. O. (2016). Concordance Rates of Adolescent Idiopathic Scoliosis in a Danish Twin Population. Spine (Phila Pa 1976), 41(19), 1503-1507. doi:10.1097/brs.0000000000001681

Takahashi, Y., Kou, I., Takahashi, A., Johnson, T. A., Kono, K., Kawakami, N., . . . Ikegawa, S. (2011). A genome-wide association study identifies common variants near LBX1 associated with adolescent idiopathic scoliosis. Nat Genet, 43(12), 1237-1240. doi:10.1038/ng.974

Tang, Q. L., Julien, C., Eveleigh, R., Bourque, G., Franco, A., Labelle, H., . . . Moreau, A. (2015). A replication study for association of 53 single nucleotide polymorphisms in ScoliScore test with adolescent idiopathic scoliosis in French-Canadian population. Spine (Phila Pa 1976), 40(8), 537- 543. doi:10.1097/brs.0000000000000807

Ward, K., Ogilvie, J. W., Singleton, M. V., Chettier, R., Engler, G., & Nelson, L. M. (2010). Validation of DNA-based prognostic testing to predict spinal curve progression in adolescent idiopathic scoliosis. Spine (Phila Pa 1976), 35(25), E1455-1464. doi:10.1097/BRS.0b013e3181ed2de1

Policy Implementation/Update Information

1/1/19 New policy developed. BCBSNC will not provide coverage for genetic testing for adolescent idiopathic scoliosis because it is considered to be investigational. BCBSNC does not provide coverage for investigational services. Medical Director review 1/1/2019. Policy noticed 1/1/2019 for effective date 4/1/2019. (sk)