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This fusion results from a failure of segmentation during the first trimester. Although six genes have previously been associated with KFS, they account for only a small proportion of cases. Among the distinct subtypes of KFS, \u201csandwich fusion\u201d involving concurrent fusion of C0-1 and C2-3 vertebrae is particularly noteworthy due to its heightened risk for atlantoaxial dislocation. In this study, we aimed to investigate novel candidate mutations in patients with \u201csandwich fusion.\u201d<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We collected and analyzed clinical data from 21 patients diagnosed with \u201csandwich fusion.\u201d Whole-exome sequencing (WES) was performed, followed by rigorous bioinformatics analyses. Our focus was on the six known KFS-related genes (\n                      <jats:italic>GDF3<\/jats:italic>\n                      ,\n                      <jats:italic>GDF6<\/jats:italic>\n                      ,\n                      <jats:italic>MEOX1<\/jats:italic>\n                      ,\n                      <jats:italic>PAX1<\/jats:italic>\n                      ,\n                      <jats:italic>RIPPLY2<\/jats:italic>\n                      , and\n                      <jats:italic>MYO18<\/jats:italic>\n                      ). Suspicious mutations were subsequently validated through in vitro experiments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our investigation revealed two novel exonic mutations in the\n                      <jats:italic>FGFR2<\/jats:italic>\n                      gene, which had not previously been associated with KFS. Notably, the c.1750A\u2009&gt;\u2009G variant in Exon 13 of\n                      <jats:italic>FGFR2<\/jats:italic>\n                      was situated within the tyrosine kinase domain of the protein, in close proximity to several established post-translational modification sites. In vitro experiments demonstrated that this certain mutation significantly impacted the function of FGFR2. Furthermore, we identified four heterozygous candidate variants in two genes (\n                      <jats:italic>PAX1<\/jats:italic>\n                      and\n                      <jats:italic>MYO18B<\/jats:italic>\n                      ) in two patients, with three of these variants predicted to have potential clinical significance directly linked to KFS.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      This study encompassed the largest cohort of patients with the unique \u201csandwich fusion\u201d subtype of KFS and employed WES to explore candidate mutations associated with this condition. Our findings unveiled novel variants in\n                      <jats:italic>PAX1<\/jats:italic>\n                      ,\n                      <jats:italic>MYO18B<\/jats:italic>\n                      , and\n                      <jats:italic>FGFR2<\/jats:italic>\n                      as potential risk mutations specific to this subtype of KFS.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13023-024-03134-9","type":"journal-article","created":{"date-parts":[[2024,4,1]],"date-time":"2024-04-01T16:18:49Z","timestamp":1711988329000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Genetic insights into the \u2018sandwich fusion\u2019 subtype of Klippel\u2013Feil syndrome: novel FGFR2 mutations identified by 21 cases of whole-exome sequencing"],"prefix":"10.1186","volume":"19","author":[{"given":"Nanfang","family":"Xu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kan-Lin","family":"Hung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongwei","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinglun","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ming","family":"Yan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7361-9494","authenticated-orcid":false,"given":"Shenglin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,1]]},"reference":[{"issue":"4","key":"3134_CR1","doi-asserted-by":"publisher","first-page":"396","DOI":"10.1097\/00007632-199702150-00008","volume":"22","author":"MN Thomsen","year":"1997","unstructured":"Thomsen MN, Schneider U, Weber M, Johannisson R, Niethard FU. 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