Genetics and Heritability of Cervical Spondylotic Myelopathy and Ossification of the Posterior Longitudinal Ligament Results of a Systematic Review

Study Design. Systematic review. Objective. To answer the following 3 clinical questions: (1) What is the evidence supporting a heritable predisposition for cervical spondylotic myelopathy (CSM) and ossification of the posterior longitudinal ligament (OPLL)? (2) What specific genetic polymorphisms have been associated with CSM and OPLL? (3) What is the evidence supporting a genetic basis for predicting postoperative outcomes for patients with CSM and OPLL? Summary of Background Data. OPLL and CSM are thought to be multifactorial conditions resulting from a combination of environmental and genetic factors. Methods. A systematic review of the English language literature was undertaken for articles published between 1980 and November 7, 2012. The strength of evidence was determined by 2 independent reviewers using the Grading of Recommendation Assessment, Development and Evaluation (GRADE) criteria for studies addressing the first question of heritability and using the criteria set forth by the HuGENet Working Group in the Venice Interim Guidelines to address the last 2 questions of genetic association. Results. Of the 118 citations identified through the initial literature search, a total of 23 articles remained after application of inclusion/exclusion criteria. The 3 family association studies related to question 1 supported the principle of an inherited predisposition to CSM and OPLL; however, the strength of evidence supporting these findings was low. Within the 19 case-control studies related to question 2, 2 single nucleotide polymorphisms (COL6A1/Intron 32(-29) and COL11A2/Intron 6(-4)) were observed at higher frequencies in OPLL cases than in controls in more than 1 study and may be associated with its development. There was insufficient evidence to support an association between CSM and any specific single nucleotide polymorphism or haplotype or to support the association of specific gene alleles with postoperative CSM outcomes. Conclusion. Existing family studies provide support for the principle of an inherited predisposition to CSM and OPLL. Multiple studies support the association of 2 collagen gene related single nucleotide polymorphisms with OPLL; however, there is insufficient evidence to support the association between CSM and any genetic polymorphism or to support a genetic predictor of surgical outcome. Summary Statements. Statement 1: Existing family studies provide support for the principle of an inherited predisposition to CSM and OPLL. Statement 2: Two SNPs related to the collagen 6A1 gene (COL6A1/Intron 32(-29)) and the collagen 11A2 gene (COL11A2/Intron 6(-4)) have been associated with OPLL in multiple studies and may be associated with its development. Statement 3: No statement can be made from the literature regarding the association of specific SNPs or haplotypes with CSM. Statement 4: No statement can be made from the literature regarding genetic predictors of surgical outcome in the context of OPLL or CSM.