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We aimed to explore the outcome of whole-exome sequencing (WES) in a cohort of 51 patients with this diagnosis.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Patients and methods<\/jats:title>\n<jats:p>Both paediatric (n = 33) and adult (n = 18) patients with cholestatic liver disease of unknown aetiology were eligible. WES was used for reassessment of 34 patients (23 children) without diagnostic genotypes in <jats:italic>ABCB11<\/jats:italic>, <jats:italic>ATP8B1<\/jats:italic>, <jats:italic>ABCB4<\/jats:italic> or <jats:italic>JAG1<\/jats:italic> demonstrable by previous Sanger sequencing, and for primary assessment of additional 17 patients (10 children). Nasopharyngeal swab mRNA was analysed to address variant pathogenicity in two families.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>WES revealed biallelic variation in 3 ciliopathy genes (<jats:italic>PKHD1<\/jats:italic>, <jats:italic>TMEM67<\/jats:italic> and <jats:italic>IFT172<\/jats:italic>) in 4 clinically unrelated index subjects (3 children and 1 adult), heterozygosity for a known variant in <jats:italic>PPOX<\/jats:italic> in one adult index subject, and homozygosity for an unreported splice-site variation in <jats:italic>F11R<\/jats:italic> in one child. Whereas phenotypes of the index patients with mutated <jats:italic>PKHD1<\/jats:italic>, <jats:italic>TMEM67<\/jats:italic>, and <jats:italic>PPOX<\/jats:italic> corresponded with those elsewhere reported, how <jats:italic>F11R<\/jats:italic> variation underlies liver disease remains unclear. Two unrelated patients harboured different novel biallelic variants in <jats:italic>IFT172<\/jats:italic>, a gene implicated in short-rib thoracic dysplasia 10 and Bardet-Biedl syndrome 20. One patient, a homozygote for <jats:italic>IFT172<\/jats:italic> rs780205001 c.167A&gt;C p.(Lys56Thr) born to first cousins, had liver disease, interpreted on biopsy aged 4y as glycogen storage disease, followed by adult-onset nephronophthisis at 25y. The other, a compound heterozygote for novel frameshift variant <jats:italic>IFT172<\/jats:italic> NM_015662.3 c.2070del p.(Met690Ilefs*11) and 2 syntenic missense variants <jats:italic>IFT172<\/jats:italic> rs776310391 c.157T&gt;A p.(Phe53Ile) and rs746462745 c.164C&gt;G p.(Thr55Ser), had a severe 8mo cholestatic episode in early infancy, with persisting hyperbilirubinemia and fibrosis on imaging studies at 17y. No patient had skeletal malformations.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>Our findings suggest association of <jats:italic>IFT172<\/jats:italic> variants with non-syndromic cholestatic liver disease.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0288907","type":"journal-article","created":{"date-parts":[[2023,7,20]],"date-time":"2023-07-20T17:52:17Z","timestamp":1689875537000},"page":"e0288907","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":8,"title":["Exome sequencing reveals IFT172 variants in patients with non-syndromic cholestatic liver disease"],"prefix":"10.1371","volume":"18","author":[{"given":"Magdal\u00e9na","family":"Ne\u0159oldov\u00e1","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"El\u017cbieta","family":"Ciara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janka","family":"Slatinsk\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1462-5920","authenticated-orcid":true,"given":"So\u0148a","family":"Fra\u0148kov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Petra","family":"Li\u0161kov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Radana","family":"Kotalov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janka","family":"Globinovsk\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2896-2108","authenticated-orcid":true,"given":"Mark\u00e9ta","family":"\u0160afa\u0159\u00edkov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucie","family":"Pfeiferov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hana","family":"Z\u016fnov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lenka","family":"Mr\u00e1zov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2599-6479","authenticated-orcid":true,"given":"Viktor","family":"Str\u00e1neck\u00fd","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alena","family":"Vrback\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ond\u0159ej","family":"Fabi\u00e1n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2486-6266","authenticated-orcid":true,"given":"Eva","family":"Sticov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Skanderov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"\u0160perl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Kalousov\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8518-6972","authenticated-orcid":true,"given":"Tom\u00e1\u0161","family":"Zima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Milan","family":"Macek","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanna","family":"Pawlowska","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A. 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