DYRK1A is commonly proposed to be a target for treating Down syndrome-associated intellectual disability (Arbones et al., 2019; Atas-Ozcan et al., 2021), but we recommend monitoring potential worsening of phenotypes in SHH-responsive tissues, such as the cerebellum, heart and bone, in preclinical studies of DYRK1A inhibitors (Goodlett et al., 2020; Jamal et al., 2022; Stringer et al., 2017a,b; Thomas et al., 2021). The gene discussed is DYRK1A; the disease is Down syndrome.