Polycomb-associated and Trithorax-associated developmental conditions-phenotypic convergence and heterogeneity

Polycomb group (PcG) and Trithorax group (TrxG) complexes represent two major components of the epigenetic machinery. This study aimed to delineate phenotypic similarities and differences across developmental conditions arising from rare variants in PcG and TrxG genes, using data-driven approaches. 462 patients with a PcG or TrxG-associated condition were identified in the DECIPHER dataset. We analysed Human Phenotype Ontology (HPO) data to identify phenotypes enriched in this group, in comparison to other monogenic conditions within DECIPHER. We then assessed phenotypic relationships between single gene diagnoses within the PcG and TrxG group, by applying semantic similarity analysis and hierarchical clustering. Finally, we analysed patient-level phenotypic heterogeneity in this group, irrespective of specific genetic diagnosis, by applying the same clustering approach. Collectively, PcG/TrxG diagnoses were associated with increased reporting of HPO terms relating to integument, growth, head and neck, limb and digestive abnormalities. Gene group analysis identified three multi-gene clusters differentiated by microcephaly, limb/digit dysmorphologies, growth abnormalities and atypical behavioural phenotypes. Patient-level analysis identified two large clusters differentiated by neurodevelopmental abnormalities and facial dysmorphologies respectively, as well as smaller clusters associated with more specific phenotypes including behavioural characteristics, eye abnormalities, growth abnormalities and skull dysmorphologies. Importantly, patient-level phenotypic clusters did not align with genetic diagnoses. Data-driven approaches can highlight pathway-level and gene-level phenotypic convergences, and individual-level phenotypic heterogeneities. Future studies are needed to understand the multi-level mechanisms contributing to both convergence and variability within this population, and to extend data collection and analyses to later-emerging health characteristics.