Identification of Rare Genetic Variants For Rotator Cuff Tearing and Repair in High-Risk Pedigrees

Background Common genetic variants with small effect sizes have been associated with rotator cuff tearing although very few rare, highly penetrant variants have been identified. The purpose of this pilot study was to identify dominant coding variants that segregated with affected individuals in pedigrees at high risk for rotator cuff tears. We hypothesize that rare variants contribute to symptomatic rotator cuff tears and that they can be identified in related cases with a full-thickness tear requiring surgical management. Methods We used the Utah Population Database (UPDB) to identify pedigrees that exhibited a significant excess of individuals who had undergone surgical repair of a full thickness rotator cuff tear. We analyzed whole exome sequence analysis to identify rare coding variants in 9 independent affected cousin pairs (first or second cousins) who had undergone arthroscopic surgery for repair of a full thickness rotator cuff tear (mean age at diagnosis 68 years). Validation of association of the candidate variants with risk for rotator cuff tearing was accomplished utilizing data from the UK Biobank and a separate cohort of unrelated cases of full thickness rotator cuff tears. Results A total of 82 rare (minor allele frequency <0.005) coding variants were identified as shared in at least one cousin pair affected with full thickness rotator cuff tearing belonging to a high-risk pedigree, which included variants in RUNX1, ADAM12, TGFBR2, APBB1, PDLIM7, LTBP1, MAP3K4 and MAP3K1. Analysis of 39 of these variants with data available in the UK Biobank (3,899 cases with rotator cuff injury and 11,697 matched controls; mean case age 59.9 years) identified a significant association with the APBB1 gene (OR=2.37, p=0.007, uncorrected). The PDLIM7 allele was found to be in significant excess in rotator cuff tear cases in a separate cohort of Utah patients with full thickness rotator cuff tears (10 carriers out of 458 independent, unrelated patients; minor allele frequency of 0.022) compared to a minor allele frequency of 0.0058 for the European (non-Finnish) control population rate (749 carriers out of 128612 tested) (chi square test: 19.3 (p<0.001). Discussion The analysis of closely related individuals with confirmed full thickness rotator cuff tears from high-risk pedigrees has identified 82 rare, shared candidate genetic predisposition coding variants. Association of the PDLIM7 allele with risk for tear was confirmed in an independent cohort of rotator cuff tears. Further analysis of the variant alleles is required for confirmation of these genes in rotator cuff tearing.