HES1 and Intellectual disability: In humans, increased expression of HES1 was reported in Down syndrome [45] and recent exome sequencing studies revealed heterozygous mutations in RBPJ and reduced expression of HES1 in two families with Adams-Oliver syndrome, associated with congenital cutis aplasia, terminal limb abnormalities (asymmetric shortening of the hands and feet in one of the families) and a range of cognitive functioning (from intellectual disability to normal) [46].