WDR73 – Galloway-Mowat Syndrome

The association between WDR73 and Galloway-Mowat syndrome is supported by multiple independent studies demonstrating the presence of pathogenic variants in patients with a consistent clinical phenotype. In several families, both consanguineous and non‐consanguineous, a range of variant types—including nonsense, missense, and frameshift mutations—have been identified. One recurrent variant, c.703C>T (p.Gln235Ter), has been observed in affected individuals and serves as a key molecular marker of the disorder (PMID:25873735).

Genetic studies have documented over 23 probands with confirmed WDR73 mutations, and segregation analyses have shown that additional affected relatives consistently inherit these variants in an autosomal recessive manner (PMID:27001912). The recurrence of the variant and the diversity of mutation types across multiple studies underscore a strong gene-disease relationship and provide robust evidence for its clinical validity.

Detailed case reports reveal that patients harboring WDR73 mutations present with a spectrum of neurological and renal manifestations. Core clinical features include cerebellar hypoplasia, intellectual disability, nephrotic syndrome, and microcephaly (PMID:25466283). The reported phenotypes are consistent across studies and align with the characteristic features of Galloway-Mowat syndrome.

Experimental data further bolster the association through functional studies in zebrafish and cellular models. Loss-of-function experiments demonstrate that depletion of WDR73 impairs brain morphogenesis and podocyte function, thereby replicating key elements of the human phenotype (PMID:25873735; PMID:36290302). These results provide moderate functional evidence that disruption of WDR73’s normal activity contributes to disease pathogenesis.

While the emphasis is on robust genetic and functional concordance, minor variability in phenotypic presentation has been noted. Nonetheless, there is no significant conflicting evidence that disputes the role of WDR73 in Galloway-Mowat syndrome. The observed phenotypic heterogeneity may reflect variable expressivity rather than a lack of pathogenic relevance.

In summary, the convergence of comprehensive genetic, segregation, and experimental data substantiates a strong association between WDR73 and Galloway-Mowat syndrome. This evidence base not only supports the diagnostic utility of screening for WDR73 mutations in patients with the syndrome’s hallmark features but also emphasizes its relevance for genetic counseling and future therapeutic research.

Key Take‑home: WDR73 mutation screening is a critical diagnostic tool in confirming Galloway-Mowat syndrome, as integrated genetic and functional evidence consistently demonstrates its central role in the disorder.

References

• Journal of medical genetics | 2015 | Nonsense mutation in the WDR73 gene is associated with Galloway-Mowat syndrome PMID:25873735
• American journal of human genetics | 2014 | Loss-of-function mutations in WDR73 are responsible for microcephaly and steroid-resistant nephrotic syndrome: Galloway-Mowat syndrome PMID:25466283
• American journal of medical genetics. Part A | 2016 | Extending the mutation spectrum for Galloway-Mowat syndrome to include homozygous missense mutations in the WDR73 gene PMID:27001912
• Biology | 2022 | WDR73 Depletion Destabilizes PIP4K2C Activity and Impairs Focal Adhesion Formation in Galloway-Mowat Syndrome PMID:36290302

Evidence Based Scoring (AI generated)