Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT)

Abstract

Purpose: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common cause of chronic kidney disease in childhood and adolescence. We aim to identify novel monogenic causes of CAKUT.

Methods: Exome sequencing was performed in 550 CAKUT-affected families.

Results: We discovered seven FOXC1 heterozygous likely pathogenic variants within eight CAKUT families. These variants are either never reported, or present in <5 alleles in the gnomAD database with ~141,456 controls. FOXC1 is a causal gene for Axenfeld-Rieger syndrome type 3 and anterior segment dysgenesis 3. Pathogenic variants in FOXC1 have not been detected in patients with CAKUT yet. Interestingly, mouse models for Foxc1 show severe CAKUT phenotypes with incomplete penetrance and variable expressivity. The FOXC1 variants are enriched in the CAKUT cohort compared with the control. Genotype-phenotype correlations showed that Axenfeld-Rieger syndrome or anterior segment dysgenesis can be caused by both truncating and missense pathogenic variants, and the missense variants are located at the forkhead domain. In contrast, for CAKUT, there is no truncating pathogenic variant, and all variants except one are located outside the forkhead domain.

Conclusion: We thereby expanded the phenotype of FOXC1 pathogenic variants toward involvement of CAKUT, which can potentially be explained by allelism.

Keywords: congenital anomalies of the kidneys and urinary tract; exome sequencing.

Fig. 1. Genotype–phenotype correlation of FOXC1 pathogenic variants between anterior segment dysgenesis and congenital anomalies of the kidneys and urinary tract (CAKUT).

There are truncating and missense pathogenic variants in anterior segment dysgenesis, and all missense pathogenic variants except one are in the forkhead (FH) domain. In contrast, in individuals with CAKUT we detected no truncating pathogenic variants, and all pathogenic variants except one are located out of the FH domain. (a) FOXC1 pathogenic variants and phenotypes published in the literature for anterior segment dysgenesis. A1. Blue horizontal boxes and lines represent pathogenic truncating variants caused by out-of-frame indels. The junction of each box and line corresponds to the start of amino acid change caused by frame shift. The right end of each line corresponds to the predicted termination position of the protein. A2. Black horizontal lines represent the extent of pathogenic truncating variants caused by nonsense pathogenic variants. The right end of each line corresponds to the predicted termination position of the protein. A3. Green vertical lines represent pathogenic in-frame indels. The location of each vertical line corresponds to the position of the in-frame change. A4. Red vertical lines represent pathogenic substitution variants caused by missense pathogenic variants. The location of each vertical line corresponds to the position of the missense pathogenic variant. All but one missense pathogenic variant was located within the FH domain. In contrast, nonsense pathogenic variants, in-frame and out-of-frame indels are not limited in FH domain. (b) FOXC1 pathogenic variants and phenotypes in CAKUT cohort. There is a spectrum of CAKUT phenotypes that is described in detail for each family. B1. Each red box represents a CAKUT family with a pathogenic missense variant. Each red arrow points to the position of the substitution. The individual ID, CAKUT and extrarenal phenotypes, nucleotide and amino acid change are presented in each box. B2. Each green box represents a CAKUT family with a pathogenic in-frame indel. Each green arrow points to the position of the indel. The individual ID, CAKUT and extrarenal phenotypes, nucleotide and amino acid change are presented in each box. There is no nonsense pathogenic variant or out-of-frame indels found in the CAKUT cohort. All pathogenic variants except one in-frame deletion are located out of FH domain. B3. Patients presented with syndromic CAKUT have FOXC1 pathogenic variants located between the start site to the end of the FH domain. Patients presented with isolated CAKUT have FOXC1 pathogenic variants downstream to the FH domain. (c) Transcript and protein domain diagram of FOXC1. C1. FOXC1 transcript NM_001453. There is no 5′ UTR and there is only one exon. C2. FOXC1_Human protein UniProtKB–Q12948. The yellow octagon represents the FH domain. Pink rectangles represent low complexity detected by the SEG program (Wootton JC and Federhen S.). AVM arteriovenous malformation, Bil bilateral, CKD chronic kidney disease, DD developmental delay, ESRD end-stage renal disease, FTT failure to thrive, LKS left kidney stone, Lt left, MCDK multicystic dysplastic kidney, n/d no data, PUV posterior urethral valve, Rt right, UPJO ureteropelvic junction obstruction, VUR vesicoureteral reflux.

Fig. 2. Pedigrees of families with CAKUT and FOXC1 pathogenic variants.

The families are sorted based on the position of their pathogenic variants. Amino acid change is included in each pedigree. CAKUT phenotypes are labeled in green. Extrarenal phenotypes are labeled in blue. AVM arteriovenous malformation, CAKUT congenital anomalies of kidney and urinary tract, CKD chronic kidney disease, ESRD end-stage renal disease, FTT failure to thrive, MCDK multicystic dysplastic kidney, n/d no data, PUV posterior urethral valve, UPJO ureteropelvic junction obstruction, VUR vesicoureteral reflux.