CAM 290

Genetic Testing for Adolescent Idiopathic Scoliosis

Category:Laboratory   Last Reviewed:July 2021
Department(s):Medical Affairs   Next Review:July 2022
Original Date:June 2013    

Description
Scoliosis is a disorder with abnormal rotation and curvature of the spine. In most cases 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, 2020).

Genetic markers have been identified related to AIS. The ScoliScore™ Test was the first clinically validated genetic test for AIS.

Regulatory Status
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. A search for “scoliosis” on the FDA website on March 9, 2020 yielded 0 relevant results (FDA, 2020). Many labs have developed specific tests that they must validate and perform in house.  These laboratory-developed tests (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.

Related Policies
20183 Interventions for Progressive Scoliosis

Policy
DNA-based prognostic testing for adolescent idiopathic scoliosis is investigational/unproven and therefore considered NOT MEDICALLY NECESSARY.
 

Rationale
AIS is the most common spinal deformity, affecting between 2-3% of children worldwide (Grauers, Einarsdottir, & Gerdhem, 2016). However, only 10% of adolescents with AIS progress to more severe curvature requiring treatment. Although males and females are affected equally, females are ten times more likely to have curve progression (Scherl, 2020).

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. Baschal 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. Novel variants in musculoskeletal collagen were found in 32% (126/391) of AIS cases compared to 17% of the control cases (146/843). The authors concluded that the AIS cases “harbor mainly non-glycine missense mutations” but noted that the genetic basis for AIS was complex with a polygenic burden of rare variants (Haller et al., 2016).

Proprietary tests, such as ScoliScore, assess the genetic basis for AIS. ScoliScore was developed by Axial Biotechnology and intended for the prediction of the likelihood of curve progression. This test is noted to be appropriate for Caucasian patients ages 9-13 with a mild to moderate curve. 53 genetic markers are evaluated to determine the risk of progression, and these markers are combined (along with the Cobb angle) into a risk score from 1-200. The test is claimed to have a 99% negative predictive value for risk of progression (VSI, 2020).

Clinical Validity and Utility
Determination of which spinal curvature 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 (SNPs) and the patient's presenting spinal curve, marketed as ScoliScore. 277 low risk females, 257 higher risk females, and 163 high risk males were sequenced and assessed using the ScoliScore algorithm. The risk model of the algorithm was standardized to identify 75% of patients as low-risk (<1% risk of progressing to a surgical curve), 24% as intermediate-risk, and 1% as high-risk. The cutoff scores were listed as <41 for low-risk, 50 for intermediate risk, and 180 for high risk. Low-risk scores had negative predictive values of 100% for the low-risk population, 99% for the higher risk females, and 97% for the high-risk males (Ward et al., 2010).

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). Ogura et al. assessed the frequency of the 53 SNPs in a 600-sample progression group and a 1114-sample non-progression group and did not find any difference in risk allele frequency between the two groups. Furthermore, the authors did not find any SNPs to correlate with the AIS curve progression.

The replication association study by Tang et al. 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. No difference in risk allele frequencies between the severe and non-severe groups was observed, as well as no difference between the severe and control groups (Tang et al., 2015).

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 ScoliScore categorized more patients as low risk (36 versus 2 percent). The authors found a positive correlation of r = 0.581 between the ScoliScore and the Cobb angle. 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 ScoliScore results did not differ between patients with and without curve progression, and the negative and positive predictive values (0.87 and 0.27 respectively) were lower in the study than in the previously published validation study by the developers of the test. The ScoliScore of the patients with curve progression was a mean of 107 and standard deviation of 55 points, and the ScoliScore of the patients without the curve progression was a mean of 102 and standard deviation of 62 points (Roye et al., 2015).

Noshchenko et al. performed a meta-analysis to identify possible predictors of spine deformity progression in AIS. 25 studies were included the analysis, and two of the eight predictors identified as “statistically significant or borderline association between severity or progression of AIS” included polymorphisms of seven genes [“(1) calmodulin 1; (2) estrogen receptor 1; (3) tryptophan hydroxylase 1; (3) insulin-like growth factor 1; (5) neurotrophin 3; (6) interleukin-17 receptor C; (7) melatonin receptor 1B,]” as well as the ScoliScore test. However, the authors remarked that the “predictive values of all these findings were limited, and the levels of evidence were low”, leading them to conclude that “this review did not reveal any methods for the prediction of progression in AIS that could be recommended for clinical use as diagnostic criteria” (Noshchenko et al., 2015).

International Scientific Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT) (Negrini et al., 2018)
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 state, “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.” SOSORT recommends prudence in using genetic tools; caution is needed to translate genetic results from research setting to clinical setting (Negrini et al., 2018).

School screening programs are recommended for the early diagnosis of idiopathic scoliosis using the Scoliometer during trunk forward bend (Adam’s test) and 5° and 7° of angle of trunk rotation should be used as criteria for referral. Screening is also recommended every time pediatricians, general practitioners and sports physicians evaluate children aged from 8 to 15 years (Negrini et al., 2018).

U.S. Preventive Services Task Force (USPSTF) (Grossman et al., 2018)
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 DNA-based testing for AIS were identified.

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

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.”

United Kingdom National Screening Committee (UK NSC, 2016)
The UK NSC recommends against screening for AIS as it is “unclear whether treating people found through screening is better than waiting for symptoms to develop” and because there is no cutoff of the forward bend test where treatment is necessary (UKNSC, 2016). 

References 

  1. AAFP. (2018). Scoliosis - Clinical Preventive Service Recommendation. Retrieved from https://www.aafp.org/patient-care/clinical-recommendations/all/scoliosis.html.  Retrieved 2/26/21, from @aafp https://www.aafp.org/patient-care/clinical-recommendations/all/scoliosis.html
  2. 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
  3. 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
  4. 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
  5. 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
  6. FDA. (2021). Devices@FDA. Retrieved from https://www.accessdata.fda.gov/scripts/cdrh/devicesatfda/index.cfm
  7. 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
  8. 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
  9. 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
  10. 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. Retrieved from https://www.ncbi.nlm.nih.gov/pubmed/14516040
  11. 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
  12. 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
  13. 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
  14. 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
  15. Noshchenko, A., Hoffecker, L., Lindley, E. M., Burger, E. L., Cain, C. M., Patel, V. V., & Bradford, A. P. (2015). Predictors of spine deformity progression in adolescent idiopathic scoliosis: A systematic review with meta-analysis. World J Orthop, 6(7), 537-558. doi:10.5312/wjo.v6.i7.537
  16. 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
  17. 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
  18. 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
  19. 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
  20. Scherl, S. (2020, 2/26/21). Adolescent idiopathic scoliosis: Clinical features, evaluation, and diagnosis - UpToDate. UpToDate. Retrieved from https://www.uptodate.com/contents/adolescent-idiopathic-scoliosis-clinical-features-evaluation-and-diagnosis
  21. 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
  22. 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
  23. 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
  24. UKNSC. (2016). The UK NSC recommendation on Adolescent Idiopathic Scoliosis screening. Retrieved from https://legacyscreening.phe.org.uk/scoliosis
  25. VSI. (2020). ADOLESCENT IDIOPATHIC SCOLIOSIS & GENETICS. Retrieved from https://www.spinemd.com/treatments/scoliosis-genetic-testing
  26. 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

Coding Section 

Codes Number Description
CPT 0004M Scoliosis, DNA analysis of 53 single nucleotide polymorphisms (SNPs), using saliva, prognostic algorithm reported as a risk score

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross and Blue Shield Association technology assessment program (TEC) and other non-affiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association.  All Rights Reserved" 

History From 2014 Forward     

07/12/2021 

Annual review, no change to policy intent. Updating rationale and references. 

07/14/2020 

Annual review, no change to policy intent, but, major revision for clarity. 

07/12/2019 

Annual review, no change to policy intent. 

07/18/2018 

Annual review, updating title to better reflect testing in policy. New title removes "DNA-Based testing" and is replaced with Genetic Testing". No other changes made. 

07/28/2017 

Annual review, no change to policy intent. Update rationale and references. 

04/25/2017 

Updated category to Laboratory. No other changes 

06/01/2016 

Annual review, no change to policy intent. Updating background, description, guidelines, rationale, references and coding section. 

06/17/2015 

Annual review, no change to policy intent. Updated rationale and references. Added coding. 

06/05/2014

Annual review. Added related policies, updated rationale and references. No change to policy intent.


Go Back