{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T19:30:21Z","timestamp":1770838221873,"version":"3.50.1"},"reference-count":15,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,12,21]],"date-time":"2025-12-21T00:00:00Z","timestamp":1766275200000},"content-version":"vor","delay-in-days":20,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,1]],"date-time":"2025-12-01T00:00:00Z","timestamp":1764547200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molec Gen &amp;amp; Gen Med"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Prenatal diagnosis of X\u2010linked hydrocephalus caused by variants in the\n                      <jats:italic>L1CAM<\/jats:italic>\n                      gene is often complicated by the identification of Variants of Uncertain Significance (VUSs). This study showcases an accelerated diagnostic workflow using artificial intelligence (AI) to rapidly interpret a novel missense variant for a family with a history of the disorder.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed exome sequencing (ES) on a male fetus with significant sonographic brain anomalies from a 29\u2010year\u2010old pregnant woman. To efficiently analyze the resulting VUSs, we used the AI tool AlphaMissense to predict their pathogenicity and prioritize them for validation. The top candidate variant was then assessed via Sanger sequencing for co\u2010segregation across eight maternal relatives. The structural impact of the mutation was visualized using the AlphaFold 3 model.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Exome sequencing identified four VUSs. AlphaMissense predicted only one,\n                      <jats:italic>L1CAM<\/jats:italic>\n                      c.1228C&gt;G (p.His410Asp), as \u2018likely pathogenic\u2019. Subsequent Sanger sequencing confirmed that this variant co\u2010segregated perfectly with the disease phenotype in the family. Based on this strong genetic evidence, the variant was reclassified from a VUS to \u2018Likely Pathogenic\u2019. Structural modeling revealed that the p.His410Asp substitution disrupts a critical salt bridge, likely compromising protein stability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our two\u2010step approach\u2014using AI for rapid VUS prioritization followed by targeted Sanger validation\u2014proved to be a highly efficient strategy. It provided a definitive and clinically actionable diagnosis that facilitated genetic counseling and enabled the family to pursue Preimplantation Genetic Testing (PGT). This workflow significantly enhances the power of genomic testing in the prenatal setting.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mgg3.70169","type":"journal-article","created":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T04:30:38Z","timestamp":1766377838000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Accelerated Identification and Preliminary Validation of a Pathogenic Missense Variant in the\n                    <scp>\n                      <i>L1CAM<\/i>\n                    <\/scp>\n                    Gene in a Pregnant Woman With Sonographic Anomalies Using\n                    <scp>AlphaMissense<\/scp>"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhihui","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Gynecology and Obstetrics Wenzhou Central Hospital  Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xuna","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Gynecology and Obstetrics Wenzhou Central Hospital  Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8102-6074","authenticated-orcid":false,"given":"Chenyang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Central Laboratory Wenzhou Central Hospital  Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rongyue","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University  Wenzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chendi","family":"Teng","sequence":"additional","affiliation":[{"name":"Department of Radiology Wenzhou Central Hospital  Zhejiang China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9531-099X","authenticated-orcid":false,"given":"Yanbin","family":"He","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Digital Technology in Medical Diagnostics  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiyan","family":"Wu","sequence":"additional","affiliation":[{"name":"Zhejiang Key Laboratory of Digital Technology in Medical Diagnostics  Hangzhou China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9971-8332","authenticated-orcid":false,"given":"Xutao","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Central Laboratory Wenzhou Central Hospital  Zhejiang China"},{"name":"Yikon Genomics Co., Ltd  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,21]]},"reference":[{"key":"e_1_2_13_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010024\u201007487\u2010w"},{"key":"e_1_2_13_3_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_13_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.2253"},{"key":"e_1_2_13_5_1","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24239"},{"key":"e_1_2_13_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_2_13_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010021\u201003819\u20102"},{"key":"e_1_2_13_8_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1741\u20104520.2005.00067.x"},{"key":"e_1_2_13_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2021.03.003"},{"key":"e_1_2_13_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.33803"},{"key":"e_1_2_13_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_13_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2890"},{"key":"e_1_2_13_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.22225"},{"key":"e_1_2_13_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/pd.978"},{"key":"e_1_2_13_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41597\u2010024\u201003327\u20108"},{"key":"e_1_2_13_16_1","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2022.810853"}],"container-title":["Molecular Genetics &amp; Genomic Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.70169","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/mgg3.70169","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/mgg3.70169","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T18:56:32Z","timestamp":1770836192000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/mgg3.70169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12]]},"references-count":15,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2025,12]]}},"alternative-id":["10.1002\/mgg3.70169"],"URL":"https:\/\/doi.org\/10.1002\/mgg3.70169","archive":["Portico"],"relation":{},"ISSN":["2324-9269","2324-9269"],"issn-type":[{"value":"2324-9269","type":"print"},{"value":"2324-9269","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12]]},"assertion":[{"value":"2025-05-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-10","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70169"}}