{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T13:53:29Z","timestamp":1781704409005,"version":"3.54.5"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T00:00:00Z","timestamp":1764288000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Primary ciliary dyskinesia (PCD) is a rare genetic disorder caused by structural or functional abnormalities of motile cilia, characterized by considerable clinical and genetic heterogeneity. Although exome sequencing (ES) can improve the diagnostic rate of PCD, more than 30% of patients with clinically suspected PCD remain undiagnosed by initial ES. The American College of Medical Genetics and Genomics (ACMG) recommends periodic reanalysis of ES data to increase the diagnostic yield.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated a 35-year-old female patient with bronchiectasis and a strong clinical suspicion of PCD from Peking Union Medical College Hospital. The patient\u2019s ES data, which had initially yielded negative results in August 2024, was reanalyzed in early 2025 employing a \u201cgenotype-phenotype-inheritance pattern\u201d strategy. A minigene assay was conducted to validate the pathogenicity of the identified\n                      <jats:italic>CFAP54<\/jats:italic>\n                      splicing variant. Variant pathogenicity was classified according to the ACMG\/AMP guidelines.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The patient had a history of rhinitis and neonatal pneumonia. Pulmonary function tests revealed moderate obstructive ventilatory dysfunction. ES reanalysis identified a homozygous variant,\n                      <jats:italic>CFAP54<\/jats:italic>\n                      (NM_001306084.2):c.6965 + 5G &amp;gt;A, which was initially classified as a variant of uncertain significance. Minigene assays confirmed that this variant induced exon 50 skipping, resulting in a frameshift and a premature termination codon (loss-of-function). This variant was subsequently reclassified as \u201cLikely Pathogenic\u201d.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study is the first to describe\n                      <jats:italic>CFAP54<\/jats:italic>\n                      :c.6965 + 5G &amp;gt;A and confirm its pathogenicity. This finding brings the total number of\n                      <jats:italic>CFAP54<\/jats:italic>\n                      -associated PCD patients to eight and the number of distinct\n                      <jats:italic>CFAP54<\/jats:italic>\n                      mutations to twelve, thereby enriching the phenotypic and genotypic spectrum of this gene. Furthermore, this effective strategy of \u201cES reanalysis + minigene verification\u201d resolved the diagnostic dilemma in initially ES-negative PCD cases, providing a replicable molecular diagnostic framework for similar scenarios.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2025.1712038","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T05:15:34Z","timestamp":1764306934000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Exome sequencing reanalysis identifies a novel likely pathogenic CFAP54 variant and expands the phenotypic and genotypic spectrum of primary ciliary dyskinesia"],"prefix":"10.3389","volume":"12","author":[{"given":"Yixuan","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wangji","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanqing","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiaoling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaogang","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai-Feng","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinlun","family":"Tian","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaping","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"449","DOI":"10.1016\/j.ccm.2016.04.008","article-title":"Primary Ciliary Dyskinesia.","volume":"37","author":"Knowles","year":"2016","journal-title":"Clin Chest Med."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1016\/j.ajhg.2019.09.022","article-title":"De Novo Mutations in FOXJ1 result in a motile ciliopathy with hydrocephalus and randomization of left\/right body asymmetry.","volume":"105","author":"Wallmeier","year":"2019","journal-title":"Am J Hum Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.arbres.2022.12.001","article-title":"Primary Ciliary dyskinesia and bronchiectasis: new data and future challenges.","volume":"59","author":"Pioch","year":"2023","journal-title":"Arch Bronconeumol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/j.semcdb.2020.11.007","article-title":"Motile cilia and airway disease.","volume":"110","author":"Legendre","year":"2021","journal-title":"Semin Cell Dev Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"77","DOI":"10.1038\/s41572-020-0209-6","article-title":"Motile ciliopathies.","volume":"6","author":"Wallmeier","year":"2020","journal-title":"Nat Rev Dis Primers."},{"key":"B6","doi-asserted-by":"publisher","first-page":"1176","DOI":"10.1378\/chest.13-1704","article-title":"Laterality defects other than situs inversus totalis in primary ciliary dyskinesia: insights into situs ambiguus and heterotaxy.","volume":"146","author":"Shapiro","year":"2014","journal-title":"Chest."},{"key":"B7","doi-asserted-by":"publisher","first-page":"459","DOI":"10.1016\/S2213-2600(21)00453-7","article-title":"The global prevalence and ethnic heterogeneity of primary ciliary dyskinesia gene variants: a genetic database analysis.","volume":"10","author":"Hannah","year":"2022","journal-title":"Lancet Respir Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"1248","DOI":"10.1183\/09031936.00001010","article-title":"Factors influencing age at diagnosis of primary ciliary dyskinesia in European children.","volume":"36","author":"Kuehni","year":"2010","journal-title":"Eur Respir J."},{"key":"B9","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1136\/adc.2009.158493","article-title":"High prevalence of primary ciliary dyskinesia in a British Asian population.","volume":"95","author":"O\u2019Callaghan","year":"2010","journal-title":"Arch Dis Child."},{"key":"B10","doi-asserted-by":"publisher","first-page":"1768","DOI":"10.1016\/j.chest.2021.02.006","article-title":"Clinical and genetic spectrum of children with primary ciliary dyskinesia in China.","volume":"159","author":"Guan","year":"2021","journal-title":"Chest."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1870","DOI":"10.1001\/jama.2014.14601","article-title":"Molecular findings among patients referred for clinical whole-exome sequencing.","volume":"312","author":"Yang","year":"2014","journal-title":"JAMA."},{"key":"B12","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/gim.2015.148","article-title":"Clinical application of whole-exome sequencing across clinical indications.","volume":"18","author":"Retterer","year":"2016","journal-title":"Genet Med."},{"key":"B13","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/S2213-2600(19)30374-1","article-title":"Primary ciliary dyskinesia in the genomics age.","volume":"8","author":"Lucas","year":"2020","journal-title":"Lancet Respir Med."},{"key":"B14","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1038\/s41525-022-00295-z","article-title":"Best practices for the interpretation and reporting of clinical whole genome sequencing.","volume":"7","author":"Austin-Tse","year":"2022","journal-title":"Npj Genomic Med."},{"key":"B15","doi-asserted-by":"publisher","first-page":"497","DOI":"10.1007\/s00415-023-11991-w","article-title":"Phenotype-driven reanalysis reveals five novel pathogenic variants in 40 exome-negative families with charcot-marie-tooth disease.","volume":"271","author":"Lin","year":"2024","journal-title":"J Neurol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1038\/gim.2017.246","article-title":"Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders.","volume":"20","author":"Wright","year":"2018","journal-title":"Genet Med."},{"key":"B17","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1038\/s41436-019-0478-1","article-title":"ACMG Laboratory Quality AssuranceCommittee. Points to consider in the reevaluation and reanalysis of genomic test results: a statement of the American College of Medical Genetics and Genomics (ACMG).","volume":"21","author":"Deignan","year":"2019","journal-title":"Genet Med."},{"key":"B18","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1136\/jmg-2022-108887","article-title":"Biallelic mutations in CFAP54 cause male infertility with severe MMAF and NOA.","volume":"60","author":"Tian","year":"2023","journal-title":"J Med Genet."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1236","DOI":"10.1007\/s11684-023-0997-7","article-title":"Lack of CFAP54 causes primary ciliary dyskinesia in a mouse model and human patients.","volume":"17","author":"Zhao","year":"2023","journal-title":"Front Med."},{"key":"B20","doi-asserted-by":"publisher","first-page":"2400790","DOI":"10.1183\/13993003.00790-2024","article-title":"Pathogenic variants in CFAP46, CFAP54, CFAP74 and CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.","volume":"64","author":"Wohlgemuth","year":"2024","journal-title":"Eur Respir J."},{"key":"B21","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1038\/nature11632","article-title":"An integrated map of genetic variation from 1,092 human genomes.","volume":"491","author":"Abecasis","year":"2012","journal-title":"Nature."},{"key":"B22","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s13073-017-0403-7","article-title":"Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation.","volume":"9","author":"Kobayashi","year":"2017","journal-title":"Genome Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"111359","DOI":"10.1016\/j.mce.2021.111359","article-title":"Curating the gnomAD database: report of novel variants in the thyrogobulin gene using in silico bioinformatics algorithms.","volume":"534","author":"Pio","year":"2021","journal-title":"Mol Cell Endocrinol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the american college of medical genetics and genomics and the association for molecular pathology.","volume":"17","author":"Richards","year":"2015","journal-title":"Genet Med."},{"key":"B25","doi-asserted-by":"publisher","first-page":"1601090","DOI":"10.1183\/13993003.01090-2016","article-title":"European Respiratory Society guidelines for the diagnosis of primary ciliary dyskinesia.","volume":"49","author":"Lucas","year":"2017","journal-title":"Eur Respir J."},{"key":"B26","volume-title":"ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2024.","author":"Durkie","year":"2024"},{"key":"B27","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1093\/humupd\/dmad003","article-title":"The impact of primary ciliary dyskinesia on female and Male fertility: a narrative review.","volume":"29","author":"Newman","year":"2023","journal-title":"Hum Reprod Update."},{"key":"B28","doi-asserted-by":"publisher","first-page":"377","DOI":"10.1146\/annurev.physiol.69.040705.141236","article-title":"Overview of structure and function of mammalian cilia.","volume":"69","author":"Satir","year":"2007","journal-title":"Annu Rev Physiol."},{"key":"B29","doi-asserted-by":"publisher","first-page":"9028","DOI":"10.1111\/jcmm.16866","article-title":"Identification of compound heterozygous DNAH11 variants in a han-chinese family with primary ciliary dyskinesia.","volume":"25","author":"Xiong","year":"2021","journal-title":"J Cell Mol Med."},{"key":"B30","doi-asserted-by":"publisher","first-page":"319","DOI":"10.1093\/clinchem\/hvad125","article-title":"Systematic minigene-based splicing analysis and tentative clinical classification of 52 CHEK2 splice-site variants.","volume":"70","author":"Sanoguera-Miralles","year":"2024","journal-title":"Clin Chem."}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1712038\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T05:15:35Z","timestamp":1764306935000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2025.1712038\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,28]]},"references-count":30,"alternative-id":["10.3389\/fmed.2025.1712038"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2025.1712038","relation":{},"ISSN":["2296-858X"],"issn-type":[{"value":"2296-858X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,28]]},"article-number":"1712038"}}