In this study, we expand and characterize the phenotypic spectrum and molecular landscape of HECW2-related neurodevelopmental disorders. Clinical characterization suggests complete penetrance for hypotonia with or without spasticity, developmental delay/intellectual disability and developmental language disorder. We also report that all pathogenic variants are missense and mainly clustered in and near the HECT domain of the protein with the recurrence of several variants. We identified two such variants which were recurrent in a large fraction of cases: p.(Arg1191Gln) and p.(Arg1330Trp), and accounted for 22.9% and 20% of cases respectively. These results will aid future molecular and clinical diagnosis and management. (By Dr. Isabelle Schrauwen, https://jmg.bmj.com/content/early/2021/07/28/jmedgenet-2021-107871 )