AI Article Synopsis

  • Congenital anomalies of the kidneys and urinary tract (CAKUT) are the leading cause of chronic kidney disease in young individuals, and some Forkhead box (FOX) transcription factors are linked to these anomalies.
  • The study conducted whole-exome sequencing on 541 families with CAKUT to compile lists of candidate genes, particularly focusing on highly expressed FOX genes during kidney development.
  • Through their analysis, researchers discovered FOXL2, FOXA2, and FOXA3 as new potential monogenic causes of CAKUT, illustrating the effectiveness of using related gene families to identify genes involved in diseases.

Article Abstract

Background: Congenital anomalies of the kidneys and urinary tract (CAKUT) constitute the most common cause of chronic kidney disease in the first three decades of life. Variants in four Forkhead box (FOX) transcription factors have been associated with CAKUT. We hypothesized that other FOX genes, if highly expressed in developing kidneys, may also represent monogenic causes of CAKUT.

Methods: We here performed whole-exome sequencing (WES) in 541 families with CAKUT and generated four lists of CAKUT candidate genes: (A) 36 FOX genes showing high expression during renal development, (B) 4 FOX genes known to cause CAKUT to validate list A, (C) 80 genes that we identified as unique potential novel CAKUT candidate genes when performing WES in 541 CAKUT families and (D) 175 genes identified from WES as multiple potential novel CAKUT candidate genes.

Results: To prioritize potential novel CAKUT candidates in the FOX gene family, we overlapped 36 FOX genes (list A) with lists C and D of WES-derived CAKUT candidates. Intersection with list C identified a de novo FOXL2 in-frame deletion in a patient with eyelid abnormalities and ureteropelvic junction obstruction, and a homozygous FOXA2 missense variant in a patient with horseshoe kidney. Intersection with list D identified a heterozygous FOXA3 missense variant in a CAKUT family with multiple affected individuals.

Conclusions: We hereby identified FOXL2, FOXA2 and FOXA3 as novel monogenic candidate genes of CAKUT, supporting the utility of a paralog-based approach to discover mutated genes associated with human disease.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9755999PMC
http://dx.doi.org/10.1093/ndt/gfab253DOI Listing

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