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dc.contributor.authorMiller, Danny E
dc.contributor.authorLee, Lin
dc.contributor.authorGaley, Miranda
dc.contributor.authorKandhaya-Pillai, Renuka
dc.contributor.authorTischkowitz, Marc
dc.contributor.authorAmalnath, Deepak
dc.contributor.authorVithlani, Avadh
dc.contributor.authorYokote, Koutaro
dc.contributor.authorKato, Hisaya
dc.contributor.authorMaezawa, Yoshiro
dc.contributor.authorTakada-Watanabe, Aki
dc.contributor.authorTakemoto, Minoru
dc.contributor.authorMartin, George M
dc.contributor.authorEichler, Evan E
dc.contributor.authorHisama, Fuki M
dc.contributor.authorOshima, Junko
dc.date.accessioned2022-05-11T10:02:51Z
dc.date.available2022-05-11T10:02:51Z
dc.date.issued2022-05-09
dc.date.submitted2022-02-05
dc.identifier.issn0022-2593
dc.identifier.otherjmedgenet-2022-108485
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/337011
dc.description.abstractBACKGROUND: Werner syndrome (WS) is an autosomal recessive progeroid syndrome caused by variants in WRN. The International Registry of Werner Syndrome has identified biallelic pathogenic variants in 179/188 cases of classical WS. In the remaining nine cases, only one heterozygous pathogenic variant has been identified. METHODS: Targeted long-read sequencing (T-LRS) on an Oxford Nanopore platform was used to search for a second pathogenic variant in WRN. Previously, T-LRS was successfully used to identify missing variants and analyse complex rearrangements. RESULTS: We identified a second pathogenic variant in eight of nine unsolved WS cases. In five cases, T-LRS identified intronic splice variants that were confirmed by either RT-PCR or exon trapping to affect splicing; in one case, T-LRS identified a 339 kbp deletion, and in two cases, pathogenic missense variants. Phasing of long reads predicted all newly identified variants were on a different haplotype than the previously known variant. Finally, in one case, RT-PCR previously identified skipping of exon 20; however, T-LRS did not detect a pathogenic DNA sequence variant. CONCLUSION: T-LRS is an effective method for identifying missing pathogenic variants. Although limitations with computational prediction algorithms can hinder the interpretation of variants, T-LRS is particularly effective in identifying intronic variants.
dc.languageen
dc.publisherBMJ
dc.subjectDiagnostics
dc.subject1506
dc.subjectnanopore sequencing
dc.subjectgenomics
dc.subjectgenetic variation
dc.titleTargeted long-read sequencing identifies missing pathogenic variants in unsolved Werner syndrome cases.
dc.typeArticle
dc.date.updated2022-05-11T10:02:51Z
prism.publicationNameJ Med Genet
dc.identifier.doi10.17863/CAM.84431
dcterms.dateAccepted2022-04-14
rioxxterms.versionofrecord10.1136/jmedgenet-2022-108485
rioxxterms.versionVoR
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2022-05-09
dc.contributor.orcidMiller, Danny E [0000-0001-6096-8601]
dc.identifier.eissn1468-6244
cam.issuedOnline2022-05-09
rioxxterms.freetoread.startdate2022-05-09
rioxxterms.freetoread.startdate2022-05-09


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