{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:44:19Z","timestamp":1792183459449,"version":"4.4.0"},"reference-count":23,"publisher":"Wiley","issue":"6","license":[{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,3,5]],"date-time":"2026-03-05T00:00:00Z","timestamp":1772668800000},"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":["Clinical Genetics"],"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    KBG syndrome (KBGS, OMIM #148050) is a rare genetic disorder caused by heterozygous truncating or missense variants in the\n                    <jats:italic>ANKRD11<\/jats:italic>\n                    gene or a deletion of 16q24.3 involving\n                    <jats:italic>ANKRD11<\/jats:italic>\n                    . While truncating variants clearly disrupt protein function, the interpretation of missense variants is more challenging, as many remain variants of uncertain significance (VUS). To address this, we evaluated PhenoScore, an open\u2010source AI\u2010based phenomics framework integrating facial recognition and medical data analysis, for predicting the pathogenicity of ANKRD11 missense variants and providing supporting evidence for variant interpretation within the ACMG framework, specifically the PP4 criterion. PhenoScore was trained on 79 individuals with truncating variants in ANKRD11 and age\u2010, sex\u2010, and ethnicity\u2010matched controls with other neurodevelopmental disorders, and its performance was compared to AlphaMissense, REVEL, and the evaluation of a clinical geneticist. Six individuals with functionally confirmed pathogenic missense variants were used for testing. PhenoScore achieved high predictive accuracy with an area under the curve (AUC) of 0.95 and a Brier score of 0.089, and pathogenic missense variants in the test set received a mean prediction score of 0.94. PhenoScore significantly outperformed REVEL (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.01), especially in cases supported by functional and clinical evidence, while no significant difference was observed compared to AlphaMissense (\n                    <jats:italic>p<\/jats:italic>\n                    \u2009=\u20090.63); importantly, the two tools showed complementary strengths. These findings suggest that PhenoScore represents a promising tool for clinical variant interpretation, as it quantifies phenotypic concordance with KBGS and provides objective evidence that can strengthen the PP4 criterion within the ACMG framework. Combined with molecular prediction tools like AlphaMissense, PhenoScore may help reduce uncertainty surrounding VUS in ANKRD11 by complementing these scores.\n                  <\/jats:p>","DOI":"10.1111\/cge.70159","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T19:08:15Z","timestamp":1772996895000},"page":"1038-1048","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Functional Data Strengthen Clinical Validation of\n                    <scp>PhenoScore<\/scp>\n                    Phenotype\u2010Guided\n                    <scp>AI<\/scp>\n                    for\n                    <scp>\n                      <i>ANKRD11<\/i>\n                    <\/scp>\n                    Missense Variants"],"prefix":"10.1111","volume":"109","author":[{"given":"Evi","family":"Andriessen","sequence":"first","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elke","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5869-0716","authenticated-orcid":false,"given":"Gholson J.","family":"Lyon","sequence":"additional","affiliation":[{"name":"New York State Institute for Basic Research in Developmental Disabilities  Staten Island New York USA"},{"name":"The Graduate Center, The City University of New York  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bert B. A.","family":"de Vries","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0329-1520","authenticated-orcid":false,"given":"Charlotte W.","family":"Ockeloen","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5648-2155","authenticated-orcid":false,"given":"Alexander J. M.","family":"Dingemans","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour Radboud University Medical Center  Nijmegen the Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,3,5]]},"reference":[{"key":"e_1_2_12_2_1","volume-title":"GeneReviews [Internet]","author":"Morel Swols D.","year":"2018"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.31597"},{"key":"e_1_2_12_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2014.253"},{"key":"e_1_2_12_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37842"},{"key":"e_1_2_12_6_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.37878"},{"key":"e_1_2_12_7_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmedgenet-2012-101288"},{"key":"e_1_2_12_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.30292"},{"key":"e_1_2_12_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2011.06.007"},{"key":"e_1_2_12_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.gim.2022.06.017"},{"key":"e_1_2_12_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/gim.2015.30"},{"key":"e_1_2_12_12_1","doi-asserted-by":"publisher","DOI":"10.1093\/jlb\/lsx038"},{"key":"e_1_2_12_13_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkg509"},{"key":"e_1_2_12_14_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkab266"},{"key":"e_1_2_12_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad989"},{"key":"e_1_2_12_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.08.016"},{"key":"e_1_2_12_17_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.adg7492"},{"key":"e_1_2_12_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588\u2010023\u201001469\u2010w"},{"key":"e_1_2_12_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.62057"},{"key":"e_1_2_12_20_1","doi-asserted-by":"publisher","DOI":"10.5334\/ojb.36"},{"key":"e_1_2_12_21_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00521-013-1524-6"},{"key":"e_1_2_12_22_1","first-page":"3484","volume-title":"Proceedings of the IEEE\/CVF Winter Conference on Applications of Computer Vision (WACV)","author":"Terh\u00f6rst P.","year":"2023"},{"key":"e_1_2_12_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkad1011"},{"key":"e_1_2_12_24_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddac289"}],"container-title":["Clinical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70159","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cge.70159","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cge.70159","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T02:47:10Z","timestamp":1778640430000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/cge.70159"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,5]]},"references-count":23,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["10.1111\/cge.70159"],"URL":"https:\/\/doi.org\/10.1111\/cge.70159","archive":["Portico"],"relation":{},"ISSN":["0009-9163","1399-0004"],"issn-type":[{"value":"0009-9163","type":"print"},{"value":"1399-0004","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,5]]},"assertion":[{"value":"2026-01-23","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-24","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-03-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}