{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T12:17:34Z","timestamp":1756383454249,"version":"3.41.2"},"reference-count":18,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2023,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>While representing a significant improvement, the introduction of next\u2010generation sequencing in genetic diagnosis also prompted new challenges. Despite widely recognized consensus guidelines for the interpretation of sequence variants, many variants remain unclassified or are discordantly interpreted. In heritable thoracic aortic aneurysms with dissection (HTAAD), most cases are caused by a heterozygous, private missense mutation, possibly contributing to the relatively common reports of variants with uncertain significance in this group. Segregation analysis necessitates advanced likelihood\u2010based methods typically inaccessible to non\u2010experts and is hampered by reduced penetrance, possible phenocopies, and non\u2010availability of DNA from deceased relatives.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>In this report, challenges in variant interpretation and the use of segregation analyses were illustrated in two families with a suspected HTAAD disorder. The R package segregatr, a novel implementation of full\u2010likelihood Bayes factor (FLB), was performed to explore the cosegregation of the variants in these families.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Using the R package segregatr, cosegregation in the reported families concluded with strong and supporting evidence for pathogenicity. Surveillance of families in a multidisciplinary team enabling systematic phenotype description for standardized segregation analysis with a robust calculation method may be imperative for reliable variant interpretation in HTAAD<jats:italic>.<\/jats:italic><\/jats:p><\/jats:sec>","DOI":"10.1002\/mgg3.2107","type":"journal-article","created":{"date-parts":[[2022,12,10]],"date-time":"2022-12-10T07:38:45Z","timestamp":1670657925000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["The use of segregation analysis in interpretation of sequence variants in SMAD3: A case report"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9382-3318","authenticated-orcid":false,"given":"Aleksandra","family":"Ratajska","sequence":"first","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Magnus D.","family":"Vigeland","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo  Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katrine Verena","family":"Wirgenes","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo  Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kirsten","family":"Krohg\u2010S\u00f8rensen","sequence":"additional","affiliation":[{"name":"Institute of Clinical Medicine University of Oslo  Oslo Norway"},{"name":"Department of Thoracic Surgery Oslo University Hospital  Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Benedicte","family":"Paus","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Oslo University Hospital  Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo  Oslo Norway"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.03.024"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2020.09.011"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20100038\u20101639612"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1159\/000152448"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2017.12.023"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.04.003"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2009.072785"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22956"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.3390\/biom10020192"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1089\/gtmb.2019.0064"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10689\u2010017\u20100017\u20107"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCRESAHA111.248161"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10689\u2010017\u20109989\u20106"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23407"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1086\/378100"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/978\u201094\u2010007\u20107893\u20101_7"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-824430-2.00008-9"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.2107","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.2107","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.2107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,19]],"date-time":"2023-08-19T01:02:11Z","timestamp":1692406931000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.2107"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,9]]},"references-count":18,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2023,2]]}},"alternative-id":["10.1002\/mgg3.2107"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.2107","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"type":"print","value":"2324-9269"},{"type":"electronic","value":"2324-9269"}],"subject":[],"published":{"date-parts":[[2022,12,9]]},"assertion":[{"value":"2022-03-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-11-03","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-12-09","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2107"}}