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Abstract: PO1344

Whole-Exome Sequencing Identifies FOXL2, FOXA2, and FOXA3 as Candidate Genes for Monogenic Congenital Anomalies of the Kidneys and Urinary Tract

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Zheng, Bixia, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Seltzsam, Steve, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Wang, Chunyan, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Schierbaum, Luca M., Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Schneider, Sophia, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Connaughton, Dervla M., Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Mann, Nina, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Tasic, Velibor, Medical Faculty Skopje, University Children’s Hospital, Skopje, Macedonia (the former Yugoslav Republic of)
  • Shril, Shirlee, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, United States
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 kidney, may also represent monogenic causes of CAKUT.

Methods

We here performed whole exome sequencing (WES) in 541 families with CAKUT and generated 4 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 FOX gene family, we overlapped 36 FOX genes (list A) with list 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.

Conclusion

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.

Funding

  • Other NIH Support