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Following negative clinical genetic testing, genome analysis identified biallelic variants in IFT57: p.(Val397Glu) and p.(Lys225Asnfs*17). IFT57 is part of complex B of the intraflagellar transport (IFT) proteins, which is an adaptor to the anterograde transport of proteins, bringing cargo from the base of the primary cilia to the tip. Variants in IFT57 have not yet been associated with BBS or human retinal degeneration, but biallelic splicing variants were associated with a distinct ciliopathy: oral-facial-digital syndrome. Using patient-derived fibroblasts, IFT57-knockouts (KO) of RPE1, and mIMCD3 cells, we showed that p.(Lys225Asnfs*17) is subjected to non-sense mediated decay, and that p.(Val397Glu) is the predominant variant which leads to cilia defects. Exogenous expression of the p.(Val397Glu) variant partially restored structural and functional primary cilia defects, and of the anterograde transport in Ift57-KO mIMCD3 cells but it did not rescue primary cilia in retinal IFT57-KO-RPE1 cells. The cell autonomous effect, likely explains the retinal dystrophy in our proband with BBS.<\/jats:p>","DOI":"10.1093\/hmg\/ddaf058","type":"journal-article","created":{"date-parts":[[2025,4,24]],"date-time":"2025-04-24T19:27:35Z","timestamp":1745522855000},"page":"1108-1122","source":"Crossref","is-referenced-by-count":4,"title":["Defective IFT57 underlies a novel cause of Bardet-Biedl syndrome"],"prefix":"10.1093","volume":"34","author":[{"given":"Alexandra","family":"Nitoiu","sequence":"first","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children , Toronto , Ontario M5G 0A4,","place":["Canada"]},{"name":"Institute of Medical Science, Temerty Faculty of Medicine, 1 King\u2019s College Circle, University of Toronto , Toronto , Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihong","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Iowa Carver College of Medicine , 200 Hawkins Drive, Iowa City, Iowa 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Erika","family":"Tavares","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children , Toronto , Ontario M5G 0A4,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janice Min","family":"Li","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children , Toronto , Ontario M5G 0A4,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kashif","family":"Ahmed","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children , Toronto , Ontario M5G 0A4,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kit","family":"Green-Sanderson","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children , Toronto , Ontario M5G 0A4,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahnoor","family":"Rashid","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children , Toronto , Ontario M5G 0A4,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shahir M","family":"Morcos","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children , Toronto , Ontario M5G 0A4,","place":["Canada"]},{"name":"Department of Molecular Genetics, Medical Sciences Building, 1 King's College, University of Toronto , Toronto , Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jayson T","family":"Maynes","sequence":"additional","affiliation":[{"name":"Department of Anesthesia and Pain Medicine, Peter Gilgan Centre for Research and Learning, 686 Bay Street, The Hospital for Sick Children , Toronto, Ontario M5G 0A4, \u00a0","place":["Canada"]},{"name":"Program in Molecular Medicine, Peter Gilgan Centre for Research and Learning, 686 Bay Street, The Hospital for Sick Children , Toronto , Ontario M5G 0A4,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric I","family":"Campos","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay Street, Hospital for Sick Children , Toronto , Ontario M5G 0A4,","place":["Canada"]},{"name":"Department of Molecular Genetics, Medical Sciences Building, 1 King's College, University of Toronto , Toronto , Ontario M5S 1A8,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Val C","family":"Sheffield","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Iowa Carver College of Medicine , 200 Hawkins Drive, Iowa City, Iowa 52242 ,","place":["United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ajoy","family":"Vincent","sequence":"additional","affiliation":[{"name":"Genetics and Genome Biology, Peter Gilgan Centre for Research and Learning, 686 Bay 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