Activating variants in PRKD2 in two families with Systemic sclerosis, and enrichment of rare variants in a sporadic series.

Systemic sclerosis (SSc) is a rare, heterogeneous autoimmune disease characterized by immune dysregulation, vasculopathy and fibrosis. While typically sporadic, SSc can in a minority of cases show familial clustering. Whole exome sequencing (WES), performed on six families with two affected members each, identified a total of 253 genes with rare, disease co-segregating variants predicted to affect protein function. Of these, we prioritized PRKD2, one of only three genes identified in two families. PRKD2 encodes Protein kinase D2: an intracellular serine-threonine kinase that amplifies T cell receptor (TCR) signaling. Both familial SSc-associated PRKD2 missense variants increased kinase activation, exerting overlapping, activating effects on TCR signaling in heterozygous knock-in Jurkat cells. A pan-PRKD inhibitor suppressed T cell activation in peripheral blood mononuclear cells from both familial SSc cases and controls. The enrichment of PRKD2 rare variants in a sporadic SSc cohort provides further support for its relevance to SSc pathogenesis. Together, these findings identify PRKD2 rare variants as potential genetic contributors to SSc, and PRKD2-mediated TCR signaling as a candidate disease-relevant and potentially targetable pathway.