{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,6]],"date-time":"2026-01-06T15:24:40Z","timestamp":1767713080545,"version":"build-2065373602"},"reference-count":29,"publisher":"BMJ","issue":"5","funder":[{"name":"USAMRAA CDMRP Neurofibromatosis Research Program","award":["W81XWH1910334"],"award-info":[{"award-number":["W81XWH1910334"]}]},{"name":"Manchester National Institute for Health Research (NIHR) Biomedical Research Centre","award":["IS- BRC-1215-20007"],"award-info":[{"award-number":["IS- BRC-1215-20007"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2023,12,7]]},"published-print":{"date-parts":[[2024,5]]},"abstract":"<jats:sec>\n                  <jats:title>Purpose<\/jats:title>\n                  <jats:p>To determine the impact of additional genetic screening techniques on the rate of detection of pathogenic variants leading to familial <jats:italic>NF2<\/jats:italic>-related schwannomatosis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We conducted genetic screening of a cohort of 168 second-generation individuals meeting the clinical criteria for <jats:italic>NF2<\/jats:italic>-related schwannomatosis. In addition to the current clinical screening techniques, targeted next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification analysis, we applied additional genetic screening techniques, including karyotype and RNA analysis. For characterisation of a complex structural variant, we also performed long-read sequencing analysis.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Additional genetic analysis resulted in increased sensitivity of detection of pathogenic variants from 87% to 95% in our second-generation <jats:italic>NF2<\/jats:italic>-related schwannomatosis cohort. A number of pathogenic variants identified through extended analysis had been previously observed after NGS analysis but had been overlooked or classified as variants of uncertain significance.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our study indicates there is added value in performing additional genetic analysis for detection of pathogenic variants that are difficult to identify with current clinical genetic screening methods. In particular, RNA analysis is valuable for accurate classification of non-canonical splicing variants. Karyotype analysis and whole genome sequencing analysis are of particular value for identification of large and\/or complex structural variants, with additional advantages in the use of long-read sequencing techniques.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1136\/jmg-2023-109586","type":"journal-article","created":{"date-parts":[[2024,2,1]],"date-time":"2024-02-01T13:21:01Z","timestamp":1706793661000},"page":"452-458","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["Improved sensitivity for detection of pathogenic variants in familial <i>NF2<\/i>-related schwannomatosis"],"prefix":"10.1136","volume":"61","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1630-1943","authenticated-orcid":false,"given":"Cristina","family":"Perez-Becerril","sequence":"first","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK"},{"name":"Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9360-8194","authenticated-orcid":false,"given":"George J","family":"Burghel","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK"},{"name":"Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claire","family":"Hartley","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charles F","family":"Rowlands","sequence":"additional","affiliation":[{"name":"Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8482-5784","authenticated-orcid":false,"given":"D Gareth","family":"Evans","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK"},{"name":"Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3184-0817","authenticated-orcid":false,"given":"Miriam J","family":"Smith","sequence":"additional","affiliation":[{"name":"Manchester Centre for Genomic Medicine, Manchester University NHS Foundation Trust, Manchester, UK"},{"name":"Division of Evolution, Infection and Genomics, School of Biological Sciences, The University of Manchester, Manchester, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2024,2,1]]},"reference":[{"key":"2025101723255538000_61.5.452.1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.29.12.841"},{"key":"2025101723255538000_61.5.452.2","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2022.05.007"},{"key":"2025101723255538000_61.5.452.3","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2010.085241"},{"key":"2025101723255538000_61.5.452.4","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.1038\/s41436-018-0384-y","article-title":"Identifying the deficiencies of current diagnostic criteria for neurofibromatosis 2 using databases of 2777 individuals with molecular testing","volume":"21","author":"Evans","year":"2019","journal-title":"Genet Med"},{"key":"2025101723255538000_61.5.452.5","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2020-107022"},{"key":"2025101723255538000_61.5.452.6","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1212\/WNL.0000000000003418","article-title":"Revisiting neurofibromatosis type 2 diagnostic criteria to exclude LZTR1-related schwannomatosis","volume":"88","author":"Smith","year":"2017","journal-title":"Neurology"},{"key":"2025101723255538000_61.5.452.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-019-0598-7"},{"key":"2025101723255538000_61.5.452.8","doi-asserted-by":"crossref","DOI":"10.1186\/1750-1172-4-16","article-title":"Neurofibromatosis type 2 (NF2): a clinical and molecular review","volume":"4","author":"Evans","year":"2009","journal-title":"Orphanet J Rare Dis"},{"key":"2025101723255538000_61.5.452.9","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2017-104519"},{"key":"2025101723255538000_61.5.452.10","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.029504"},{"key":"2025101723255538000_61.5.452.11","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1002\/gcc.20876","article-title":"Effects of splicing mutations on NF2-transcripts: transcript analysis and information theoretic predictions","volume":"50","author":"Ellis","year":"2011","journal-title":"Genes Chromosomes Cancer"},{"key":"2025101723255538000_61.5.452.12","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-8628(19980518)77:3<228::AID-AJMG8>3.0.CO;2-L"},{"key":"2025101723255538000_61.5.452.13","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1002\/humu.24261","article-title":"Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes","volume":"42","author":"Perez-Becerril","year":"2021","journal-title":"Hum Mutat"},{"key":"2025101723255538000_61.5.452.14","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025101723255538000_61.5.452.15","unstructured":"Ellard S , Baple EL , Callaway A , et al . ACGS best practice guidelines for variant classification in rare disease 2020. Recommendations ratified by ACGS quality subcommittee on 4TH February 2020: Association for clinical Genomic science; 2020."},{"key":"2025101723255538000_61.5.452.16","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.3.393"},{"key":"2025101723255538000_61.5.452.17","doi-asserted-by":"crossref","DOI":"10.1038\/s41467-019-10717-9","article-title":"Characterising the loss-of-function impact of 5\u2019 untranslated region variants in 15,708 individuals","volume":"11","author":"Whiffin","year":"2020","journal-title":"Nat Commun"},{"key":"2025101723255538000_61.5.452.18","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2003.016774"},{"key":"2025101723255538000_61.5.452.19","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.ebiom.2016.04.005","article-title":"Comprehensive RNA analysis of the NF1 gene in classically affected NF1 affected individuals meeting NIH criteria has high sensitivity and mutation negative testing is reassuring in Isolated cases with pigmentary features only","volume":"7","author":"Evans","year":"2016","journal-title":"EBioMedicine"},{"key":"2025101723255538000_61.5.452.20","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-021-00865-4"},{"key":"2025101723255538000_61.5.452.21","doi-asserted-by":"crossref","DOI":"10.1186\/s13073-021-00883-1","article-title":"Whole-genome sequencing with long reads reveals complex structure and origin of structural variation in human genetic variations and somatic mutations in cancer","volume":"13","author":"Fujimoto","year":"2021","journal-title":"Genome Med"},{"key":"2025101723255538000_61.5.452.22","doi-asserted-by":"crossref","DOI":"10.1186\/s13073-018-0606-6","article-title":"Complex structural variants in mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing","volume":"10","author":"Sanchis-Juan","year":"2018","journal-title":"Genome Med"},{"key":"2025101723255538000_61.5.452.23","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1053\/j.gastro.2022.08.041","article-title":"Noncoding aberrations in mismatch repair genes underlie a substantial part of the missing heritability in lynch syndrome","volume":"163","author":"Te Paske","year":"2022","journal-title":"Gastroenterology"},{"key":"2025101723255538000_61.5.452.24","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05513-w"},{"key":"2025101723255538000_61.5.452.25","doi-asserted-by":"crossref","first-page":"1093","DOI":"10.1093\/nar\/gkac653","article-title":"Efficient detection and assembly of non-reference DNA sequences with synthetic long reads","volume":"50","author":"Meleshko","year":"2022","journal-title":"Nucleic Acids Res"},{"key":"2025101723255538000_61.5.452.26","unstructured":"Vilella AJ . Next generation sequencing V1.9.0 2018. n.d. Available: http:\/\/bit.ly\/ngsspecs"},{"key":"2025101723255538000_61.5.452.27","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1038\/s41551-023-01081-7","article-title":"Profiling of repetitive RNA sequences in the blood plasma of patients with cancer","volume":"7","author":"Reggiardo","year":"2023","journal-title":"Nat Biomed Eng"},{"key":"2025101723255538000_61.5.452.28","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms16027"},{"key":"2025101723255538000_61.5.452.29","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1038\/s41586-022-05035-y","article-title":"Transcriptome variation in human tissues revealed by long-read sequencing","volume":"608","author":"Glinos","year":"2022","journal-title":"Nature"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2023-109586","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T06:26:08Z","timestamp":1760768768000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2023-109586"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,1]]},"references-count":29,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2024,4,19]]},"published-print":{"date-parts":[[2024,5]]}},"alternative-id":["10.1136\/jmg-2023-109586"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2023-109586","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"type":"print","value":"0022-2593"},{"type":"electronic","value":"1468-6244"}],"subject":[],"published":{"date-parts":[[2024,2,1]]}}}