AI-Based Facial Phenotyping Supports a Shared Molecular Axis in PACS1-, PACS2-, and WDR37-Related Syndromes

Abstract

AI-based facial analysis; Schuurs-Hoeijmakers syndrome; Dysmorphology

Anàlisi facial basada en intel·ligència artificial; Síndrome de Schuurs-Hoeijmakers; Dismorfologia

Análisis facial basado en inteligencia artificial; Síndrome de Schuurs-Hoeijmakers; Dismorfología

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.

This research was funded by Spanish Ministry of Health-ISCIII Fondo de Investigación Sanitaria (FIS) [Ref. PI23/01370, to F.J.R. and J.P.] and co-founded by European Union; Diputación General de Aragón-FEDER: European Social Fund [Reference Group B32_20R, to J.P.]; University of Zaragoza [JIUZ2023-SAL-06 to A.L.-P].