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A collapsing gene burden test was performed to analyze rare protein-altering variants using case\u2013control statistics. Since no single gene achieved statistical significance, targeted exon sequencing was performed for 24 genes with the smallest<jats:italic>p<\/jats:italic>values, in an independent replication cohort of unrelated severely affected females with AIS and sex-matched controls (N\u2009=\u200996 each). An excess of rare, potentially protein-altering variants was noted in one particular gene,<jats:italic>FAT3<\/jats:italic>, although it did not achieve statistical significance. Independently, we sequenced the exomes of all members of a rare multiplex family of three affected sisters and unaffected parents. All three sisters were compound heterozygous for two rare protein-altering variants in<jats:italic>FAT3<\/jats:italic>. The parents were single heterozygotes for each variant. The two variants in the family were also present in our discovery cohort. A second validation step was done, using another independent replication cohort of 258 unrelated AIS patients having reach their skeletal maturity and 143 healthy controls to genotype nine<jats:italic>FAT3<\/jats:italic>gene variants, including the two variants previously identified in the multiplex family: p.L517S (rs139595720) and p.L4544F (rs187159256). Interestingly, two<jats:italic>FAT3<\/jats:italic>variants, rs139595720 (genotype A\/G) and rs80293525 (genotype C\/T), were enriched in severe scoliosis cases (4.5% and 2.7% respectively) compared to milder cases (1.4% and 0.7%) and healthy controls (1.6% and 0.8%). Our results implicate<jats:italic>FAT3<\/jats:italic>as a new candidate gene in the etiology of AIS.<\/jats:p>","DOI":"10.1038\/s41598-022-16620-6","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T10:03:15Z","timestamp":1658224995000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Identification of FAT3 as a new candidate gene for adolescent idiopathic scoliosis"],"prefix":"10.1038","volume":"12","author":[{"given":"Dina","family":"Nada","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C\u00e9dric","family":"Julien","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simon","family":"Papillon-Cavanagh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacek","family":"Majewski","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed","family":"Elbakry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wesam","family":"Elremaly","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E.","family":"Samuels","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Moreau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"16620_CR1","doi-asserted-by":"publisher","first-page":"15030","DOI":"10.1038\/nrdp.2015.30","volume":"1","author":"JC Cheng","year":"2015","unstructured":"Cheng, J. 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