A Multi-State Structural Genomics Approach Enables Large-Scale, Mechanistic, and Context-Specific Classification of...

Genetic variation in ATP Binding Cassette Subfamily C Member 6 (ABCC6) can cause both pseudoxanthoma elasticum (PXE) and generalized arterial calcification of infancy (GACI). Despite both diseases being rare, there are already 930 distinct missense variants in ABCC6 reported, 87% of which are of uncertain clinical significance (VUS). New approaches are needed to interpret and classify these VUS mechanistically.

We developed 3D protein models of ABCC6 in three functionally relevant conformations to calculate the structural effects of variants and identify 3D mutational hotspots. With this and additional functional information, we categorized variants in a mechanistic ontology based on which critical functions of ABCC6 they impact. We then compared PXE and GACI-associated variants.

We identified two three-dimensional hotspots of pathogenic variants and six specific functions of ABCC6 which variants impact. From this, we propose a mechanism for pathogenicity for 41% of VUS according to their impacted function, 30 of which could be reclassified as Likely Pathogenic from our non-clinical data. Finally, we found slight differences between PXE and GACI-associated variants.

The mechanistic information we present will guide future research to better address calcification disorders and understand genetic variants. Further, our VUS reclassification will improve the diagnosis of ABCC6-driven diseases, shortening diagnostic odysseys. We believe that computational structural genomics approaches will soon take prominence in genomics data interpretation.