Novel variants in the stem cell niche factor WNT2B define the disease phenotype as a congenital enteropathy with ocular dysgenesis

This study investigates the clinical and molecular consequences of novel WNT2B variants in patients presenting with severe, neonatal-onset diarrhea. WNT2B is a critical signaling protein involved in stem cell maintenance and embryologic development, and its dysfunction has previously been linked to congenital enteropathies.

The researchers performed whole-exome sequencing on a patient with severe, neonatal-onset diarrhea and extra-intestinal symptoms. They utilized histological analysis of intestinal and gonadal tissues, RNAscope to assess WNT2B expression, and in silico homology modeling to predict the functional impact of the identified missense variant on protein structure and post-translational modification.

The researchers identified a patient with compound heterozygous WNT2B variants (a frameshift and a missense mutation). The patient exhibited severe gastrointestinal symptoms, including gastric oxyntic atrophy and colonic crypt paucity, alongside ocular anomalies (corneal clouding) and a 46,XX testicular difference/disorder of sexual development (DSD). Structural modeling suggests that the missense variant disrupts a conserved glycine residue essential for WNT2B palmitoylation, a post-translational modification required for proper secretion and binding to Frizzled receptors. This study expands the phenotypic spectrum of WNT2B-related disorders to include an oculo-intestinal syndrome, with potential implications for gonadal development.

Understanding the role of WNT2B in human development provides critical insights into the pathogenesis of congenital diarrheas and enteropathies (CODEs). By linking specific genetic variants to both intestinal and extra-intestinal manifestations, this research helps clinicians better characterize and manage these rare, complex developmental syndromes, while highlighting the importance of WNT signaling in maintaining stem cell niches across multiple organ systems.