Genetic “drivers” of the autoimmune disease systemic sclerosis: What can rare families tell us?

Systemic sclerosis (SSc) is a relatively rare rheumatological condition characterized by vascular, immune and connective tissue dysregulation. There are currently no effective disease modifying therapies, nor have any genetic “causes” been identified yet. While typically sporadic, SSc can in rare cases recur in families. Using whole exome sequencing (WES) data from the members of six such families, we set out to identify and functionally test for potential “drivers” of SSc: variants with demonstrable effects on protein and cell function. We allowed for both genetic heterogeneity (different genes in the different families), and for transmission of SSc as a di- or oligo-genic trait (more than one gene per family). Intriguingly, variants in the PRKD2 gene, identified in two of the six families, both seem to cause increased T cell activation, with overlapping but not identical effects on T cell receptor-mediated signaling. In each of these families, the PRKD2 variant is “paired” with a variant in a candidate gene that causes a Mendelian disease with some phenotypic overlap with SSc: NT5E (CD73, responsible for extracellular adenosine production) in one family, and STING1 (the central effector of the cGAS/STING danger-sensing pathway) in the second. I will discuss our efforts to try and decipher whether, and how, each of these genes may be able to contribute to the pathogenesis and phenotypic variability of SSc.