@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} } @article {516, title = {Whole-Exome Sequencing Identifies Causative Mutations in Families with Congenital Anomalies of the Kidney and Urinary Tract.}, journal = {J Am Soc Nephrol}, volume = {29}, year = {2018}, month = {2018 Sep}, pages = {2348-2361}, abstract = {

BACKGROUND: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most prevalent cause of kidney disease in the first three decades of life. Previous gene panel studies showed monogenic causation in up to 12\% of patients with CAKUT.

METHODS: We applied whole-exome sequencing to analyze the genotypes of individuals from 232 families with CAKUT, evaluating for mutations in single genes known to cause human CAKUT and genes known to cause CAKUT in mice. In consanguineous or multiplex families, we additionally performed a search for novel monogenic causes of CAKUT.

RESULTS: In 29 families (13\%), we detected a causative mutation in a known gene for isolated or syndromic CAKUT that sufficiently explained the patient{\textquoteright}s CAKUT phenotype. In three families (1\%), we detected a mutation in a gene reported to cause a phenocopy of CAKUT. In 15 of 155 families with isolated CAKUT, we detected deleterious mutations in syndromic CAKUT genes. Our additional search for novel monogenic causes of CAKUT in consanguineous and multiplex families revealed a potential single, novel monogenic CAKUT gene in 19 of 232 families (8\%).

CONCLUSIONS: We identified monogenic mutations in a known human CAKUT gene or CAKUT phenocopy gene as the cause of disease in 14\% of the CAKUT families in this study. Whole-exome sequencing provides an etiologic diagnosis in a high fraction of patients with CAKUT and will provide a new basis for the mechanistic understanding of CAKUT.

}, issn = {1533-3450}, doi = {10.1681/ASN.2017121265}, author = {van der Ven, Amelie T and Connaughton, Dervla M and Ityel, Hadas and Mann, Nina and Nakayama, Makiko and Chen, Jing and Vivante, Asaf and Hwang, Daw-Yang and Schulz, Julian and Braun, Daniela A and Schmidt, Johanna Magdalena and Schapiro, David and Schneider, Ronen and Warejko, Jillian K and Daga, Ankana and Majmundar, Amar J and Tan, Weizhen and Jobst-Schwan, Tilman and Hermle, Tobias and Widmeier, Eugen and Ashraf, Shazia and Amar, Ali and Hoogstraaten, Charlotte A and Hugo, Hannah and Kitzler, Thomas M and Kause, Franziska and Kolvenbach, Caroline M and Dai, Rufeng and Spaneas, Leslie and Amann, Kassaundra and Stein, Deborah R and Baum, Michelle A and Somers, Michael J G and Rodig, Nancy M and Ferguson, Michael A and Traum, Avram Z and Daouk, Ghaleb H and Bogdanovic, Radovan and Staji{\'c}, Natasa and Soliman, Neveen A and Kari, Jameela A and El Desoky, Sherif and Fathy, Hanan M and Milosevic, Danko and Al-Saffar, Muna and Awad, Hazem S and Eid, Loai A and Selvin, Aravind and Senguttuvan, Prabha and Sanna-Cherchi, Simone and Rehm, Heidi L and MacArthur, Daniel G and Lek, Monkol and Laricchia, Kristen M and Wilson, Michael W and Mane, Shrikant M and Lifton, Richard P and Lee, Richard S and Bauer, Stuart B and Lu, Weining and Reutter, Heiko M and Tasic, Velibor and Shril, Shirlee and Hildebrandt, Friedhelm} }