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

Area of Science:

• Genetics
• Developmental Biology
• Clinical Medicine

Background:

• Mowat-Wilson syndrome (MWS) is a rare genetic disorder.
• It is caused by pathogenic variants in the Zinc Finger E-Box-Binding Homeobox 2 (ZEB2) gene.
• ZEB2 is crucial for development and encodes multiple functional domains.

Purpose of the Study:

• To comprehensively review pathogenic ZEB2 variants and their correlation with MWS clinical characteristics.
• To investigate the role of specific ZEB2 protein domains and non-domain regions in MWS manifestations.
• To analyze genotype-phenotype relationships for improved understanding and management of MWS.

Main Methods:

• Systematic literature search (2001-2023) and analysis of unpublished datasets.
• Examination of 191 individuals with reported clinical features and genotypic data.
• Correlation of genetic defects in ZEB2 with clinical presentations.

Main Results:

• Nonsense ZEB2 variants in exon 8, encoding key protein domains, are frequently observed and linked to multi-organ involvement, particularly gastrointestinal findings.
• Variants in exons 3, 4, and 5, affecting non-domain regions, are associated with MWS facial gestalt, brain malformations, developmental delay, and intellectual disability.
• Frameshift (45%) and nonsense (38%) variants are the most common deleterious ZEB2 mutations in MWS.

Conclusions:

• Exon 8 of the ZEB2 gene plays a critical role in protein structure and function, with variants leading to significant clinical manifestations.
• Specific ZEB2 variant locations correlate with distinct MWS phenotypes, aiding in understanding disease mechanisms.
• Understanding genotype-phenotype relationships in MWS is vital for prognosis, clinical surveillance, and genetic counseling.