Clinical and genotypic characterization of SETD5-related disorders using Human Phenotype Ontology-based profiling

Loss-of-function variants in SETD5 (Set domain-containing protein 5) are a recognized cause of an autosomal dominant neurodevelopmental disorder. However, emerging experimental and in silico evidence suggests that SETD5 may have broader developmental roles, and systematically curated human data remain limited. This study aimed to characterize the systemic and extracerebral manifestations of SETD5 -related disorders and to refine the expanding clinical spectrum. We conducted a retrospective study of six unrelated children with pathogenic or likely pathogenic SETD5 variants. Clinical phenotypes were mapped using Human Phenotype Ontology (HPO) terms, and compared with previously reported cohorts. Four novel frameshift insertions or deletions of fewer than 10 base pairs were identified, along with two previously reported pathogenic variants. Consistent with prior reports, all patients presented with global developmental delay, with partial developmental catch-up during follow-up. HPO-based phenotypic profiling included previously reported congenital heart defects and feeding difficulties, as well as additional, underrepresented structural anomalies such as congenital diaphragmatic hernia, renal anomalies, and airway anomalies. Our findings support an expanded multisystem spectrum of SETD5 -related disorders, extending beyond a neurodevelopmental manifestations to include multisystem anomalies. These findings, together with longitudinal developmental observations, highlight the importance of early recognition and multidisciplinary clinical surveillance.