Inter-individual gene variants associated with trabecular bone plasticity: A step forward in the personal genomics of degenerative bone disease.

Continuing tissue destruction in osteoarthrosis is maintained by molecular pathways related to an unbalanced chondrocyte metabolism, the loss of reactive oxygen species (ROS) homeostasis, increase catabolism in a degraded matrix and the limited response to growth factors due to cell aging. Rare deleterious gene variants driving relevant molecular pathways may play a key role in the pathogenesis and genetic control of common diseases and may also influence the common gene variants observed in GWAS. We use molecular profiling technologies based on massive sequencing of genes to interrogate clinical samples for a variety of molecules involved in the pathogenesis pathways of OA and also to derive new insights for drug targeting discovery at an early stage of the disease. By whole-exome sequencing performed in OA patients with extreme phenotypes and in non-related individuals without clinical evidence of OA, the most predominant of the rare gene variants found were non-synonymous single-nucleotide variants (SNV) from exonic DNA regions and with missense functional effects predicting a moderate impact on protein function. A total of 629, 577, and 639 gene variants for the TPF, COA, and ANHNF patients, respectively, were found not to be shared with the 20 non-disease-related individuals. After subtraction of the 306 variants shared among the OA patients, we obtained the individual profiles of 323, 271, and 333 gene variants, for the TPF, COA, and ANHNF patients, respectively. After filtering by the bioinformatics, genetic, and biological criteria established to assess the clinical consequences, comparative analysis of trio sequences using integrative genome visualization tool clearly demonstrate the differences between patients. Analysis of the collagen gene variants identified 78, 20, and 43 genetic collagen variants for the three extreme phenotypes. Rare gene variants encoding for proteins that are less abundant in the trabecular bone matrix, together with those responsible for the control and regulation of bone turnover and plasticity of subchondral trabecular bone, play important roles in OA and help to define the clinical phenotype.

Whole-exome sequencing analysis in twin sibling males with an anterior cruciate ligament rupture.

Familial predisposition is among the major genetic risk factors for non-contact musculoskeletal tissue injuries. Personal genome sequence shows that different polymorphism profiles may account for the number and the degree of injuries and the recovery time. Genotyping studies allow investigation into genome factors with potential impact on pathogenesis of non-contact ligament injuries. We have studied a family with twin sibling males surgically diagnosed of an anterior cruciate ligament non-contact rupture and non-affected progenitors (father and mother) were subjected to whole exome sequencing (WES) analysis. WES analysis previously carried out on 16 individuals, without ACL injury medical records, were also included in this study for single nucleotide variants (SNVs) and small insertions and deletions detection (indels), variant filtering and to prioritize variants relative to the disease. WES analysis to identify SNVs and indels was performed using open web-based bioinformatics tools. A set of 11 new variants shared by family members can be associated to ACL non-contact injury, including SerpinA11, ARSI, NOCHT4, EPB41, FDFT1, POMC, KIF26A, OLFML2B, ATG7, FAH and WDR6. All of them, except ATG7 and WDR6, have shown a damaging predictive pattern by combinatorial standard predictive scores. In combination to the identified SNVs of EPB41 and SerpinA11 genes, ACTL7A gene showed a predicted deleterious variant reinforcing the idea these variants impact on of fibroblast-like cells deformability and ECM misbalance, Differential gene expression and RNA sequencing analysis will help to understand the combined participation of these protein coding genes in ACL non-contact injuries.