Conserved patterns across ion channels correlate with variant pathogenicity and clinical phenotypes

Area of Science:

• Genetics and Molecular Biology
• Structural Biology
• Biophysics

Background:

• Genetic variants in ion channels can lead to disease by altering protein function.
• Predicting the pathogenicity of ion channel variants is challenging due to limited understanding of structure-function relationships.
• Systematic identification of variant properties linked to pathogenicity is needed for clinical decision-making.

Purpose of the Study:

• To systematically identify biological properties associated with variant pathogenicity across major ion channel families.
• To develop and apply a novel 3D spatial distance scoring approach for variant analysis.
• To correlate identified properties with clinical phenotypes and functional assays.

Main Methods:

• Curated large datasets of pathogenic and population variants for 30 ion channel subunits with available structures.
• Computed 163 structural features and tested for pathogenic variant enrichment.
• Developed a 3D spatial distance scoring method to compare variant distributions.
• Validated findings using independent datasets and expert-curated data.

Main Results:

• Pore residue properties and proximity to the pore axis are significantly enriched in pathogenic variants.
• Strongest enrichment observed for pore-lining and alpha-helix residues near the pore axis.
• Pore hydrophobicity is strongly associated with variant pathogenicity.
• Identified properties correlate with clinical phenotypes (e.g., seizure onset) and in vitro functional assays.

Conclusions:

• Biological properties associated with ion channel malfunction have been identified.
• These properties correlate with in vitro functional readouts and patient clinical phenotypes.
• Future clinical decision support algorithms for variant pathogenicity prediction are feasible.