162635 20251017144621.0 doi 10.3390/ijms26167964 sideral 145174 ART-2025-145174 eng del Rincón, Julia AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes 2025 Access copy available to the general public Unrestricted Despite significant advances in gene discovery, the molecular basis of many rare genetic disorders remains poorly understood. The concept of disease modules, clusters of functionally related genes whose disruption leads to overlapping phenotypes, offers a valuable framework for interpreting these conditions. However, identifying such relationships remains particularly challenging in ultra-rare syndromes due to the limited number of documented cases. We hypothesized that AI-based facial phenotyping could aid in identifying shared molecular mechanisms by detecting phenotypic convergence among clinically related syndromes. To test this, we used Schuurs–Hoeijmakers syndrome (SHMS; OMIM #615009), caused by a recurrent de novo variant in PACS1, as a model to explore potential phenotypic and functional associations with PACS2-related disorder (DEE66; OMIM #618067) and WDR37-related disorder (NOCGUS; OMIM #618652). Facial photographs of individuals with SHMS were analyzed using the DeepGestalt and GestaltMatcher algorithms. In addition to consistently recognizing SHMS as a distinct clinical entity, the algorithms frequently matched DEE66 and NOCGUS, suggesting a shared facial gestalt. Binary comparisons further confirmed overlapping craniofacial features among the three disorders. These findings were supported by literature review, indicating clinical overlapping and potential functional associations. Overall, our results confirm the presence of consistent facial similarities among PACS1-, PACS2-, and WDR37-related syndromes and highlight the utility of AI-driven facial phenotyping as a complementary tool for uncovering clinically relevant relationships in ultra-rare genetic disorders. info:eu-repo/grantAgreement/ES/DGA-FEDER/B32-20R info:eu-repo/grantAgreement/ES/ISCIII/PI23-01370 info:eu-repo/grantAgreement/ES/UZ/JIUZ-2023-SAL-06 info:eu-repo/semantics/openAccess by https://creativecommons.org/licenses/by/4.0/deed.es info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion Gil-Salvador, Marta Universidad de Zaragoza (orcid)0000-0001-6858-1575 Lucia-Campos, Cristina Universidad de Zaragoza Acero, Laura Universidad de Zaragoza Trujillano, Laura Arnedo, María Universidad de Zaragoza (orcid)0000-0001-9962-2157 Pamplona, Pilar Universidad de Zaragoza Ayerza-Casas, Ariadna Universidad de Zaragoza (orcid)0000-0002-0023-8137 Puisac, Beatriz Universidad de Zaragoza (orcid)0000-0003-0170-7326 Ramos, Feliciano J. Universidad de Zaragoza (orcid)0000-0002-5732-2209 Pié, Juan Universidad de Zaragoza (orcid)0000-0003-3203-6254 Latorre-Pellicer, Ana Universidad de Zaragoza (orcid)0000-0002-4703-6620 1012 410 Universidad de Zaragoza Dpto. Farmac.Fisiol.y Med.L.F. Área Fisiología 1007 610 Universidad de Zaragoza Dpto. Medicina, Psiqu. y Derm. Area Medicina 1011 670 Universidad de Zaragoza Dpto. Microb.Ped.Radio.Sal.Pú. Área Pediatría 26, 16 (2025), 7964 [13 pp.] Int. j. mol. sci. International Journal of Molecular Sciences 1661-6596 2189728 http://zaguan.unizar.es/record/162635/files/texto_completo.pdf Versión publicada 2582626 http://zaguan.unizar.es/record/162635/files/texto_completo.jpg?subformat=icon icon Versión publicada oai:zaguan.unizar.es:162635 articulos driver 2025-10-17-14:21:59 ARTICLE