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Most implicated loci have been identified from candidate gene-based approach using case-control association settings. Here, we leverage a hypothesis-free whole genome sequencing in two two unrelated families (Family A and B) each with twins with a history of recurrent ACL ruptures acquired playing rugby as their primary sport, aimed to elucidate biologically relevant function-altering variants and genetic modifiers in ACL rupture. Family A monozygotic twin males (Twin 1 and Twin 2) both sustained two unilateral non-contact ACL ruptures of the right limb while playing club level touch rugby. Their male sibling sustained a bilateral non-contact ACL rupture while playing rugby union was also recruited. The father had sustained a unilateral non-contact ACL rupture on the right limb while playing professional amateur level football and mother who had participated in dancing for over 10 years at a social level, with no previous ligament or tendon injuries were both recruited. Family B monozygotic twin males (Twin 3 and Twin 4) were recruited with Twin 3 who had sustained a unilateral non-contact ACL rupture of the right limb and Twin 4 sustained three non-contact ACL ruptures (two in right limb and one in left limb), both while playing provincial level rugby union. Their female sibling participated in karate and swimming activities; and mother in hockey (4 years) horse riding (15 years) and swimming, had both reported no previous history of ligament or tendon injury. Variants with potential deleterious, loss-of-function and pathogenic effects were prioritised. Identity by descent, molecular dynamic simulation and functional partner analyses were conducted. We identified, in all nine affected individuals, including twin sets, non-synonymous SNPs in three genes: <jats:italic>COL12A1<\/jats:italic> and <jats:italic>CATSPER2<\/jats:italic>, and <jats:italic>KCNJ12<\/jats:italic> that are commonly enriched for deleterious, loss-of-function mutations, and their dysfunctions are known to be involved in the development of chronic pain, and represent key therapeutic targets. Notably, using Identity By Decent (IBD) analyses a long shared identical sequence interval which included the LINC01250 gene, around the telomeric region of chromosome 2p25.3, was common between affected twins in both families, and an affected brother\u2019. Overall gene sets were enriched in pathways relevant to ACL pathophysiology, including complement\/coagulation cascades (p = 3.0e-7), purine metabolism (p = 6.0e-7) and mismatch repair (p = 6.9e-5) pathways. Highlighted, is that this study fills an important gap in knowledge by using a WGS approach, focusing on potential deleterious variants in two unrelated families with a historical record of ACL rupture; and providing new insights into the pathophysiology of ACL, by identifying gene sets that contribute to variability in ACL risk.<\/jats:p>","DOI":"10.1371\/journal.pone.0274354","type":"journal-article","created":{"date-parts":[[2022,10,6]],"date-time":"2022-10-06T17:31:11Z","timestamp":1665077471000},"page":"e0274354","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":7,"title":["A whole genome sequencing approach to anterior cruciate ligament rupture\u2013a twin study in two unrelated families"],"prefix":"10.1371","volume":"17","author":[{"given":"Daneil","family":"Feldmann","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6174-6066","authenticated-orcid":true,"given":"Christian D.","family":"Bope","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon","family":"Patricios","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emile R.","family":"Chimusa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malcolm","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0950-286X","authenticated-orcid":true,"given":"Alison V.","family":"September","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,10,6]]},"reference":[{"issue":"1","key":"pone.0274354.ref001","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1186\/s12889-020-08890-4","article-title":"Modelling and prediction of global non-communicable diseases.","volume":"20","author":"Y Wang","year":"2020","journal-title":"BMC public health."},{"issue":"9838","key":"pone.0274354.ref002","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/S0140-6736(12)61031-9","article-title":"Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy","volume":"380","author":"IM Lee","year":"2012","journal-title":"Lancet"},{"key":"pone.0274354.ref003","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1002\/art.41571","article-title":"Prevalence, Deaths, and Disability-Adjusted Life Years Due to Musculoskeletal Disorders for 195 Countries and Territories 1990\u20132017.","volume":"73","author":"S Safiri","year":"2021","journal-title":"Arthritis Rheumatol"},{"issue":"6","key":"pone.0274354.ref004","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.jsams.2008.07.005","article-title":"Incidence of anterior cruciate ligament injury and other knee ligament injuries: a national population-based study.","volume":"12","author":"SM Gianotti","year":"2009","journal-title":"J Sci Med Sport"},{"issue":"3","key":"pone.0274354.ref005","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/S1050-6411(02)00022-6","article-title":"Consequences of a ligament injury on neuromuscular function and relevance to rehabilitation\u2014Using the anterior cruciate ligament-injured knee as model.","volume":"12","author":"E. 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