@article {977, title = {Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT).}, journal = {Genet Med}, volume = {22}, year = {2020}, month = {2020 10}, pages = {1673-1681}, 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 = {Child, Eye Abnormalities, Forkhead Transcription Factors, Heterozygote, Humans, Kidney, Phenotype, Urinary Tract}, issn = {1530-0366}, doi = {10.1038/s41436-020-0844-z}, author = {Wu, Chen-Han Wilfred and Mann, Nina and Nakayama, Makiko and Connaughton, Dervla M and Dai, Rufeng and Kolvenbach, Caroline M and Kause, Franziska and Ottlewski, Isabel and Wang, Chunyan and Kl{\"a}mbt, Verena and Seltzsam, Steve and Lai, Ethan W and Selvin, Aravind and Senguttuva, Prabha and Bodamer, Olaf and Stein, Deborah R and El Desoky, Sherif and Kari, Jameela A and Tasic, Velibor and Bauer, Stuart B and Shril, Shirlee and Hildebrandt, Friedhelm} }