{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:43:40Z","timestamp":1767141820115,"version":"3.48.0"},"reference-count":17,"publisher":"BMJ","issue":"4","content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2025,2,6]]},"published-print":{"date-parts":[[2025,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Clinicians often deal with copy-number variants of unknown significance (CNVUS) when managing neurodevelopmental disorders (NDDs). Variant classification is often complemented with textual comments, while the American College of Medical Genetics and Genomics (ACMG)\/Clinical Genome Resource (ClinGen) numerical scores are rarely reported. Our aim was to determine if the application of ACMG\/ClinGen scoring and inheritance\/segregation studies are relevant for the reclassification of CNVUS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrieved 167 CNVUS (112 duplications, 55 heterozygous deletions) from test reports of 141 patients with NDD in a 5-year period. None of those testing reports included ACMG\/ClinGen scoring information for the CNVUS. One clinical and one laboratorial geneticist independently applied the ACMG\/ClinGen scoring system for CNVs. Final scores\/categories were assessed for potential modification when adding inheritance\/segregation criteria.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>138 (83%) of the CNVUS retained the VUS classification, 14 (8%) changed to benign and 15 (9%) to (likely) pathogenic. Variants deemed benign (11 duplications, 3 deletions) mostly overlapped with ClinGen-established benign regions or were common in the general population; variants deemed (likely) pathogenic (all deletions) were either associated with unrelated autosomal recessive\/later-onset autosomal dominant (AD) conditions, or with an AD NDD phenotype in a single case. Inheritance studies were available for 20 (12%) variants (17 inherited, 3 de novo), and none led to a change in classification. A simulation showed that adding inheritance information would also not change the classification of any other variant.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Application of the ACMG\/ClinGen scoring system led by itself to reclassification of 17% of VUS, despite a very low increase in diagnostic yield (1\/141, 0.7%). Additionally, segregation\/inheritance studies in CNVUS were mostly irrelevant in most NDD cases, challenging their routine broad application in clinical practice.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmg-2024-110144","type":"journal-article","created":{"date-parts":[[2025,2,16]],"date-time":"2025-02-16T13:20:37Z","timestamp":1739712037000},"page":"298-302","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Enhancing clinical decision-making for CNVs of uncertain significance in neurodevelopmental disorders: the relevance (or uselessness) of scoring and segregating"],"prefix":"10.1136","volume":"62","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7863-0406","authenticated-orcid":false,"given":"Jorge Diogo","family":"Da Silva","sequence":"first","affiliation":[{"name":"Medical Genetics Centre Dr. Jacinto Magalh\u00e3es, Santo Ant\u00f3nio University Hospital Center, Porto, Portugal"},{"name":"Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal"},{"name":"ICVS\/3B\u2019s - PT Government Associate Laboratory, Braga\/Guimar\u00e3es, Portugal"},{"name":"UMIB - Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal"}]},{"given":"Nuno","family":"Maia","sequence":"additional","affiliation":[{"name":"UMIB - Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal"},{"name":"School of Health, Polytechnic of Porto, Porto, Portugal"}]},{"given":"Paula","family":"Jorge","sequence":"additional","affiliation":[{"name":"UMIB - Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal"},{"name":"Cytogenetics Laboratory, Department of Microscopy, ICBAS - Institute of Biomedical Sciences Abel Salazar, UPorto - University of Porto, Porto, Portugal"}]},{"given":"Vanessa","family":"Sousa","sequence":"additional","affiliation":[{"name":"UMIB - Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal"},{"name":"Cytogenetics Laboratory, Department of Microscopy, ICBAS - Institute of Biomedical Sciences Abel Salazar, UPorto - University of Porto, Porto, Portugal"}]},{"given":"Nataliya","family":"Tkachenko","sequence":"additional","affiliation":[{"name":"Medical Genetics Centre Dr. Jacinto Magalh\u00e3es, Santo Ant\u00f3nio University Hospital Center, Porto, Portugal"},{"name":"UMIB - Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal"}]},{"given":"Ana Rita","family":"Soares","sequence":"additional","affiliation":[{"name":"Medical Genetics Centre Dr. Jacinto Magalh\u00e3es, Santo Ant\u00f3nio University Hospital Center, Porto, Portugal"},{"name":"UMIB - Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal"},{"name":"ITR-Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal"},{"name":"Genetyca-ICM, Atrys, Porto, Portugal"}]}],"member":"239","published-online":{"date-parts":[[2025,2,16]]},"reference":[{"key":"2025123016400612000_62.4.298.1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pneurobio.2012.07.005"},{"key":"2025123016400612000_62.4.298.2","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3181f8baad"},{"key":"2025123016400612000_62.4.298.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpn.2013.04.010"},{"key":"2025123016400612000_62.4.298.4","doi-asserted-by":"publisher","DOI":"10.1136\/jmg-2022-108962"},{"key":"2025123016400612000_62.4.298.5","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2023.100995"},{"key":"2025123016400612000_62.4.298.6","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"2025123016400612000_62.4.298.7","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-019-0686-8"},{"key":"2025123016400612000_62.4.298.8","doi-asserted-by":"crossref","DOI":"10.3389\/fped.2021.526779","article-title":"Genetic Testing in Neurodevelopmental Disorders","volume":"9","author":"Savatt","year":"2021","journal-title":"Front Pediatr"},{"key":"2025123016400612000_62.4.298.9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMsr1406261"},{"key":"2025123016400612000_62.4.298.10","doi-asserted-by":"crossref","DOI":"10.1038\/s41598-022-19274-6","article-title":"Chromosomal microarray analyses from 5778 patients with neurodevelopmental disorders and congenital anomalies in Brazil","volume":"12","author":"Krepischi","year":"2022","journal-title":"Sci Rep"},{"key":"2025123016400612000_62.4.298.11","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-06045-0"},{"key":"2025123016400612000_62.4.298.12","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt958"},{"key":"2025123016400612000_62.4.298.13","doi-asserted-by":"crossref","DOI":"10.3389\/fgene.2020.577152","article-title":"Mastermind: A Comprehensive Genomic Association Search Engine for Empirical Evidence Curation and Genetic Variant Interpretation","volume":"11","author":"Chunn","year":"2020","journal-title":"Front Genet"},{"key":"2025123016400612000_62.4.298.14","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2009.03.010"},{"key":"2025123016400612000_62.4.298.15","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1113"},{"key":"2025123016400612000_62.4.298.16","doi-asserted-by":"publisher","DOI":"10.1002\/humu.24291"},{"key":"2025123016400612000_62.4.298.17","doi-asserted-by":"publisher","DOI":"10.1111\/cge.12460"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg-2024-110144","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,31]],"date-time":"2025-12-31T00:40:40Z","timestamp":1767141640000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg-2024-110144"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,2,16]]},"references-count":17,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2025,3,20]]},"published-print":{"date-parts":[[2025,4]]}},"alternative-id":["10.1136\/jmg-2024-110144"],"URL":"https:\/\/doi.org\/10.1136\/jmg-2024-110144","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"type":"print","value":"0022-2593"},{"type":"electronic","value":"1468-6244"}],"subject":[],"published":{"date-parts":[[2025,2,16]]}}}