Interestingly, TITIN interacts with adenylate kinase (AK) proteins,36 and the Inositol 1,4,5-Trisphosphate Receptor Type 3 encoded by ITPR3 is regulated by PTEN.45 Relatedly, using the same filtration criteria implemented to prioritize TTN, we did not find any variants in other genes known to be associated with CS, namely SDHx, AKT1, PIK3CA, SEC23B, and USF3,46–49 in our patients with germline TTN variants. Here, ITPR3 is linked to Cowden syndrome 1.