Towards definition of the genetic basis of rotator cuff tears: genome wide association studies versus exome sequencing studies

Background: degenerative rotator cuff tear (RCT) is a musculoskeletal disease characterized by shoulder pain and functional impairment without history of trauma. A vast literature describing RCT suggests that a genetic predisposition likely underlies this condition. Many studies have identified RCT susceptibility loci, but due to genetic and phenotypic heterogeneity observed across individuals, very few loci were subsequently replicated. Research on genetic predisposition to atraumatic RCT has relied on classical linkage studies or genome-wide association studies (GWAS) to identify candidate genes with common susceptibility variants. Although the observation of such common variants is informative, they can only explain a small fraction of the predicted RCT heritability, suggesting a considerable contribution would come from rare and highly penetrant variants. Purpose: the purpose of this study wasto test the hypothesis that rare genetic variants cause or predispose to RCT. The long-term objective is to understand the molecular basis of RCTs to delineate targeted therapies and preventive measures to reduce both direct and indirect costs for the healthcare system. Methods: We searched for families composed by patient affected by bilateral atraumatic full thickness RCT documented at magnetic resonance imaging, and with at least a 1st degree relative affected by bilateral RCT too. Families had to respect inclusion and exclusion criteria. Also their unaffected 1st degree relatives were studied. All patient suffering RCT underwent arthroscopic repair procedure in Orthopaedic Department of our Institution. One 10-ml blood sample was drawn from all included subjects to perform a whole exome sequencing. Exome sequencing was performed by an external laboratory DanteLab SRL (Pizzoli, AQ), 4 while genetic analysis was conducted in collaboration with Genetics Department of our Institution. Results: a family of four individuals was enrolled. Two subjects (affected son and his mother) had bilateral atraumatic RCT. Two subjects (unaffected son and his father) denied shoulder pathology. Patients with atraumatic RCT underwent reparative surgery. Notably, the male patient underwent surgery in 2021, the mother before the start of our study. The healthy brother participated in the exome sequencing study, while the father will be studied in the future with a family segregation analysis by the Sanger method. In our study we found four rare gene variants associated with atraumatic RCT: COL23A1: p.P458S, JARID2: p.Q454P, MDC1: p.G207Pfs*3, HDAC10: p.P426L. Conclusion: this is the first study to evaluate the genetic predisposition of RCT through whole exome sequency study on a family. It is a first step in an ongoing investigation of genetic basis and to delineate preventive measures and targeted therapy for RCTs. To ensure the validity of RCT susceptibility genes identified through this study, it will be imperative that these findings be validate in a larger external cohort