Implication ofFOXD2dysfunction in syndromic congenital anomalies of the kidney and urinary tract (CAKUT) (original) (raw)
Related papers
Nephrology Dialysis Transplantation, 2021
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.
2020
Congenital anomalies of the kidney and urinary tract (CAKUT) occur in 5%-10% of the population. About 50%-60% of affected patients have malformations of other organ systems including the heart and cardiovascular system, gastrointestinal tract, central nervous system, skeletal system, lung, face, genito-reproductive system, abdominal wall, chromosomal abnormalities, multiple congenital anomalies (MCA) and others. CAKUT is a major cause of chronic kidney disease (CKD) especially in children accounting for about 50% of cases. CAKUT should be suspected in children with anomalies of other organ systems, MCA, chromosomal aberrations, and in newborns with major abnormalities of the ear lobe. Awareness of this association is essential in the early diagnosis and management of CAKUT to prevent renal damage and chronic kidney disease.