TWIST1 and Cowden syndrome 1: We yielded a 43% diagnostic success rate using the presented approach, highlighting the high occurrence of pathogenic variants within “classic” CS genes, i.e., FGFR1, FGFR2, FGFR3, TWIST1, and TCF12. Moreover, we have critically summarized the applied diagnostic methods (Figure 1) and proposed the optimized, cost-effective diagnostic algorithm, which may be helpful in a daily diagnostic routine of various CS’ types (Figure 2).