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Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including\n                    <jats:italic>HYDIN<\/jats:italic>\n                    .\n                    <jats:italic>HYDIN<\/jats:italic>\n                    -related PCD is underdiagnosed due to the presence of a pseudogene,\n                    <jats:italic>HYDIN2<\/jats:italic>\n                    , with 98% sequence homology to\n                    <jats:italic>HYDIN<\/jats:italic>\n                    . This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include\n                    <jats:italic>HYDIN<\/jats:italic>\n                    . We have used a combined approach of SR-NGS with bioinformatic masking of\n                    <jats:italic>HYDIN2<\/jats:italic>\n                    , and state-of-the-art long-read Nanopore sequencing (LR_NGS), together with analysis of respiratory cilia including transmission electron microscopy and immunofluorescence to address the underdiagnosis of\n                    <jats:italic>HYDIN<\/jats:italic>\n                    as a cause of PCD. Bioinformatic masking of\n                    <jats:italic>HYDIN2<\/jats:italic>\n                    after SR-NGS facilitated the detection of biallelic\n                    <jats:italic>HYDIN<\/jats:italic>\n                    variants in 15 of 437 families, but compromised the detection of copy number variants. Supplementing testing with LR-NGS detected\n                    <jats:italic>HYDIN<\/jats:italic>\n                    deletions in 2 families, where SR-NGS had detected a single heterozygous\n                    <jats:italic>HYDIN<\/jats:italic>\n                    variant. LR-NGS was also able to confirm true homozygosity in 2 families when parental testing was not possible. Utilising a combined genomic diagnostic approach, biallelic\n                    <jats:italic>HYDIN<\/jats:italic>\n                    variants were detected in 17 families from 242 genetically confirmed PCD cases, comprising 7% of our PCD cohort. This represents the largest reported\n                    <jats:italic>HYDIN<\/jats:italic>\n                    cohort to date and highlights previous underdiagnosis of\n                    <jats:italic>HYDIN<\/jats:italic>\n                    -associated PCD. Moreover this provides further evidence for the utility of LR-NGS in diagnostic testing, particularly for regions of high genomic complexity.\n                  <\/jats:p>","DOI":"10.1038\/s41431-024-01599-7","type":"journal-article","created":{"date-parts":[[2024,4,11]],"date-time":"2024-04-11T10:01:55Z","timestamp":1712829715000},"page":"1074-1085","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["Combined approaches, including long-read sequencing, address the diagnostic challenge of HYDIN in primary ciliary dyskinesia"],"prefix":"10.1038","volume":"32","author":[{"given":"Andrew","family":"Fleming","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miranda","family":"Galey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lizi","family":"Briggs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8477-530X","authenticated-orcid":false,"given":"Matthew","family":"Edwards","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8368-5994","authenticated-orcid":false,"given":"Claire","family":"Hogg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shibu","family":"John","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sam","family":"Wilkinson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3648-6084","authenticated-orcid":false,"given":"Ellie","family":"Quinn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ranjit","family":"Rai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"Burgoyne","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andy","family":"Rogers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitali P.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Griffin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Muller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0580-2478","authenticated-orcid":false,"given":"Siobhan B.","family":"Carr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael R.","family":"Loebinger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8701-9975","authenticated-orcid":false,"given":"Jane S.","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anand","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Jose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3163-6293","authenticated-orcid":false,"given":"Hannah M.","family":"Mitchison","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amelia","family":"Shoemark","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6096-8601","authenticated-orcid":false,"given":"Danny E.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7780-4707","authenticated-orcid":false,"given":"Deborah J.","family":"Morris-Rosendahl","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,11]]},"reference":[{"key":"1599_CR1","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1016\/j.jpeds.2020.11.040","volume":"230","author":"A Horani","year":"2021","unstructured":"Horani A, Ferkol TW. 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