ZEB2 Gene Pathogenic Variants Across Protein-Coding Regions and Impact on Clinical Manifestations: A Review

Mowat–Wilson syndrome (MWS) is a rare multi-system genetic disorder caused by variants in the Zinc Finger E-Box-Binding Homeobox 2 (ZEB2) gene. ZEB2 is an autosomal dominant gene containing ten exons within the canonical version transcript (Isoform: O60315-1). The ZEB2 gene encodes six functional domains and seven non-domain regions. This review provides a comprehensive summary of pathogenic variants and their associated MWS clinical characteristics, focusing on ZEB2 pathogenic variants, functional protein domains and non-domain regions with clinical features. A systematic literature search from 2001 to 2023 and of unpublished datasets found 191 individuals with reported clinical features and genotypic data. Genetic defects and clinical manifestations were examined that presumably impact on the structure and function of the ZEB2 gene, thereby causing multiple developmental defects with corresponding clinical presentation. This study found more nonsense ZEB2 variants observed within exon 8, which encodes four of the six protein domains: the CtBP-interacting domain (CID), homeodomain (HD), SMAD-binding domain (SMD or SBD) and part of the N-terminal zinc finger cluster (N-ZF), suggesting exon 8 plays a crucial role in this protein structure and function with multi-organ involvement. Exon 8 defects were found to be statistically more represented for gastrointestinal findings when compared to other exons, while frameshift defects were more often seen for the typical MWS face in non-domain protein regions. In contrast, nonsense or other types of variants in exons 3, 4 and 5 which encode only flanking non-domain regions were observed more often, compared with other exons excluding exon 8, to be specifically involved in the MWS facial gestalt, brain malformations, developmental delay and intellectual disability. Deleterious ZEB2 frameshift (45%) and nonsense (38%) gene variants were most often observed with deletions at 6% and missense at 5%. The genotype and clinical relationships in MWS can provide insights into prognosis, morbidity, clinical surveillance strategies and counseling of family members.