FOXD2 – Congenital Anomaly of Kidney and Urinary Tract

FOXD2 has emerged as a compelling candidate in the etiology of syndromic congenital anomalies of the kidney and urinary tract (CAKUT). Two independent studies have identified rare, homozygous variants in FOXD2 in multiplex families with a presumed autosomal recessive inheritance pattern (PMID:36993625, PMID:38154558).

In these studies, genetic analysis revealed a frameshift variant, c.789dup (p.Gly264ArgfsTer?), alongside missense variants segregating with disease in affected families. Such findings support a strong genetic contribution to CAKUT, with robust segregation observed across five unrelated families.

Complementary functional studies bolster the genetic evidence. CRISPR/Cas9-mediated Foxd2 knockout mouse models developed bilateral renal pelvis dilation, papillary atrophy, and extrarenal abnormalities. These models recapitulate the human phenotype, underscoring the pathogenic impact of FOXD2 loss-of-function.

Further mechanistic insights were provided by transcriptomic analyses in cellular models, which identified significant alterations in key developmental regulators such as PAX2 and WNT4. These data suggest that perturbations in the PAX2-WNT4 signaling axis likely underpin the renal and extrarenal anomalies associated with FOXD2 dysfunction.

In summary, the convergence of genetic and experimental evidence supports a strong gene‑disease association for FOXD2 in autosomal recessive syndromic CAKUT. Key take‑home sentence: Incorporating FOXD2 in genetic testing panels offers critical diagnostic insights for patients with congenital kidney and urinary tract anomalies, thereby enhancing clinical decision‑making and management.

References

• medRxiv • 2023 • Implication of FOXD2 dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT) PMID:36993625
• medRxiv • 2023 • Genetic and Functional Assessment of FOXD2 in CAKUT PMID:38154558

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