Genetic Characterization in Familial Rotator Cuff Tear: An Exome Sequencing Study

SIMPLE SUMMARY: Rotator cuff tear is the most common musculoskeletal disorders in the working population. Family members of patients with rotator cuff disease have a significant higher risk of tendon tears than general population. The etiology is multifactorial, and its pathogenesis is not completely understood. It is expected that multiple gene variants contribute to disease susceptibility but, in some instances, a few main rare variants can be responsible for the clinical manifestations. We performed exome sequencing on a family (4 members) to identify rare gene variants predisposing to the development of rotator cuff tears. Rare variants in common between the two affected subjects were selected. Using the predictions in silico tools, the candidate variants were segregated by Sanger sequencing. Based on the risk of being damaging and on the potential role in rotator cuff etiopathogenesis, three candidate genes for rotator cuff tears were prioritized: COL23A1, EMILIN3 and HDAC10. These findings suggest that performing exome sequencing in other rotator cuff tears families will possibly lead to the identification of major candidate genes for the disease. The genes identified in the present study could be confirmed in a larger cohort of patients with rotator cuff tears, even if they have no family history. ABSTRACT: Background: multiple gene variants seem to contribute to rotator cuff (RC) tear susceptibility. The aim of the study is to perform an exome sequencing analysis within a family to identify rare gene variants predisposing to the development of RC tear. Material and methods: the exome sequencing was conducted in a family consisting of four individuals, two healthy and the remaining ones with bilateral RC tears. Variants in common among the two affected subjects were selected, and those in common with the healthy subject and those with a frequency >1% were removed. The potential pathogenicity of the variants was investigated using the predictions of several in silico tools from VarSome. Results: the exome sequencing yielded approximately 600,000 variants per patient, subsequently filtered according to frequency <1% and absence of association with other diseases. Removing variants common with the healthy subject, 348 rare variants among 248 genes were identified. Based on the risk of damaging, three candidate genes for RC tear were found: COL23A1, EMILIN3, and HDAC10. Conclusion: this is the first whole-exome sequencing analysis within a family to explore genetic predisposition in RC tear. The results reveal the presence of common damaging variants among affected individuals in the COL23A1, EMILIN3, and HDAC10 genes.