Combined skeletal dysplasia and vasculopathy phenotypes associated with in-frame intragenic deletion in PRKACA

Pathogenic missense variants in PRKACA cause craniofacial, skeletal, and cardiac defects similar to Ellis-van Creveld syndrome. We report an individual with a previously unreported, de novo 3 amino acid deletion in PRKACA, identified on trio genome sequencing, and phenotypic features including severe neonatal hypotonia, appendicular skeletal abnormalities, osteopenia, aortic dilation, coronary dilation and vascular tortuosity. To assess this variant's effects, we performed in vitro and in vivo studies, generated an in-silico model, and assessed cell ciliation in induced pluripotent stem cells from the patient. Although the protein product of the PRKACA (PKA-Cα) 3 amino acid deletion variant is catalytically active, it shows reduced interaction with the regulatory subunits of PKA (particularly type II), resulting in overactivation of the PKA pathway and/or an inability to initiate hedgehog signaling. The deletion affects a key portion of PKA-C important for substrate tethering. Patient-derived iPSC have reduced ciliation compared to controls. Collectively, this supports that the PRKACA variant is pathogenic, and we propose that it is causal for our patient's unique skeletal dysplasia and vasculopathy phenotypes. This expands the phenotypic spectrum of pathogenic variants in PRKACA and suggests that affected individuals may require periodic screening for aortic and coronary dilation as well as osteopenia.