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

Area of Science:

• Epigenetics and Developmental Biology
• Human Genetics and Genomics
• Computational Biology

Background:

• Polycomb group (PcG) and Trithorax group (TrxG) complexes are key epigenetic regulators essential for development.
• Rare genetic variants in PcG and TrxG genes can lead to a spectrum of developmental disorders.
• Understanding phenotypic variability within these conditions is crucial for diagnosis and management.

Purpose of the Study:

• To delineate phenotypic similarities and differences in developmental conditions associated with rare variants in PcG and TrxG genes.
• To identify common and distinct phenotypic features across different genetic diagnoses within the PcG/TrxG group.
• To explore patient-level phenotypic heterogeneity irrespective of specific genetic diagnosis.

Main Methods:

• Utilized the DECIPHER dataset, analyzing 462 patients with PcG or TrxG-associated conditions.
• Applied Human Phenotype Ontology (HPO) analysis to identify enriched phenotypes.
• Employed semantic similarity analysis and hierarchical clustering for gene group and patient-level analyses.

Main Results:

• PcG/TrxG diagnoses were linked to increased HPO terms for integument, growth, head/neck, limb, and digestive abnormalities.
• Gene group analysis revealed three clusters based on microcephaly, limb/digit dysmorphologies, growth, and behavioral phenotypes.
• Patient-level analysis identified clusters defined by neurodevelopmental and facial dysmorphologies, independent of genetic diagnosis.

Conclusions:

• Data-driven approaches effectively highlight pathway-level phenotypic convergence and individual-level heterogeneity in PcG/TrxG-related disorders.
• Phenotypic clusters at the patient level did not consistently align with specific genetic diagnoses.
• Further research is needed to elucidate the mechanisms underlying phenotypic convergence and variability and to track long-term health characteristics.