Validation experiments in a point mutant mouse model revealed that HES7, an effector gene of NOTCH, encodes a HES transcriptional repressor, and when a single dose of HES7 is insufficient, it can cause defects in embryonic somatic segment development by interfering with fibroblast growth factor (FGF) expression and eventually cause CS malformations in mice. Here, HES7 is linked to Cowden syndrome 1.