{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,6]],"date-time":"2026-05-06T21:29:14Z","timestamp":1778102954124,"version":"3.51.4"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T00:00:00Z","timestamp":1630540800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK076683"],"award-info":[{"award-number":["DK076683"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"NIH","doi-asserted-by":"publisher","award":["DK088767"],"award-info":[{"award-number":["DK088767"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,9,22]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1093\/ndt\/gfab253","type":"journal-article","created":{"date-parts":[[2021,9,2]],"date-time":"2021-09-02T14:57:08Z","timestamp":1630594628000},"page":"1833-1843","source":"Crossref","is-referenced-by-count":11,"title":["Whole-exome sequencing identifies<i>FOXL2<\/i>,<i>FOXA2<\/i>and<i>FOXA3<\/i>as candidate genes for monogenic congenital anomalies of the kidneys and urinary tract"],"prefix":"10.1093","volume":"37","author":[{"given":"Bixia","family":"Zheng","sequence":"first","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"},{"name":"Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University , Nanjing, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Steve","family":"Seltzsam","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunyan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Schierbaum","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sophia","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen-Han Wilfred","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rufeng","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dervla M","family":"Connaughton","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makiko","family":"Nakayama","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nina","family":"Mann","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natasa","family":"Stajic","sequence":"additional","affiliation":[{"name":"Department of Pediatric Nephrology, Institute for Mother and Child Health Care , Belgrade, Serbia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shrikant","family":"Mane","sequence":"additional","affiliation":[{"name":"Department of Genetics, Yale University School of Medicine , New Haven, CT, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stuart B","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Urology, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Velibor","family":"Tasic","sequence":"additional","affiliation":[{"name":"Medical Faculty of Skopje, University Children's Hospital , Skopje, Macedonia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyun Joo","family":"Nam","sequence":"additional","affiliation":[{"name":"Department of Biological and Environmental Science, Texas A&M University at Commerce , Commerce, TX, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shirlee","family":"Shril","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Friedhelm","family":"Hildebrandt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Boston Children\u2019s Hospital, Harvard Medical School , Boston, MA, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2021,9,2]]},"reference":[{"key":"2022121608271746800_gfab253-B1","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1111\/nep.12402","article-title":"Congenital anomalies of the kidney and urinary tract genetics in mice and men","volume":"20","author":"Caruana","year":"2015","journal-title":"Nephrology (Carlton)"},{"key":"2022121608271746800_gfab253-B2","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/gim.2016.131","article-title":"Whole-exome sequencing in the molecular diagnosis of individuals with congenital anomalies of the kidney and urinary tract and identification of a new causative gene","volume":"19","author":"Bekheirnia","year":"2017","journal-title":"Genet Med"},{"key":"2022121608271746800_gfab253-B3","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s40348-021-00112-0","article-title":"Molecular causes of congenital anomalies of the kidney and urinary tract (CAKUT)","volume":"8","author":"Kohl","year":"2021","journal-title":"Mol Cell Pediatr"},{"key":"2022121608271746800_gfab253-B4","doi-asserted-by":"crossref","first-page":"2348","DOI":"10.1681\/ASN.2017121265","article-title":"Whole-exome sequencing identifies causative mutations in families with congenital anomalies of the kidney and urinary tract","volume":"29","author":"van der Ven","year":"2018","journal-title":"J Am Soc Nephrol"},{"key":"2022121608271746800_gfab253-B5","doi-asserted-by":"crossref","first-page":"4558","DOI":"10.1242\/dev.112672","article-title":"Fox transcription factors: from development to disease","volume":"143","author":"Golson","year":"2016","journal-title":"Development"},{"key":"2022121608271746800_gfab253-B6","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1038\/s41577-018-0048-9","article-title":"Forkhead box transcription factors as context-dependent regulators of lymphocyte homeostasis","volume":"18","author":"Zaiss","year":"2018","journal-title":"Nat Rev Immunol"},{"key":"2022121608271746800_gfab253-B7","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/0092-8674(89)90133-5","article-title":"The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo","volume":"57","author":"Weigel","year":"1989","journal-title":"Cell"},{"key":"2022121608271746800_gfab253-B8","doi-asserted-by":"crossref","first-page":"1673","DOI":"10.1038\/s41436-020-0844-z","article-title":"Phenotype expansion of heterozygous FOXC1 pathogenic variants toward involvement of congenital anomalies of the kidneys and urinary tract (CAKUT)","volume":"22","author":"Wu","year":"2020","journal-title":"Genet Med"},{"key":"2022121608271746800_gfab253-B9","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1016\/j.ajhg.2009.05.005","article-title":"Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations","volume":"84","author":"Stankiewicz","year":"2009","journal-title":"Am J Hum Genet"},{"key":"2022121608271746800_gfab253-B10","doi-asserted-by":"crossref","first-page":"2251","DOI":"10.1002\/ajmg.a.38293","article-title":"Renal anomalies and lymphedema distichiasis syndrome. A rare association?","volume":"173","author":"Jones","year":"2017","journal-title":"Am J Med Genet A"},{"key":"2022121608271746800_gfab253-B11","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/ng.3512","article-title":"Mutations in nuclear pore genes NUP93, NUP205 and XPO5 cause steroid-resistant nephrotic syndrome","volume":"48","author":"Braun","year":"2016","journal-title":"Nat Genet"},{"key":"2022121608271746800_gfab253-B12","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature13127","article-title":"Guidelines for investigating causality of sequence variants in human disease","volume":"508","author":"MacArthur","year":"2014","journal-title":"Nature"},{"key":"2022121608271746800_gfab253-B13","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The sequence Alignment\/Map format and SAMtools","volume":"25","author":"Li","year":"2009","journal-title":"Bioinformatics"},{"key":"2022121608271746800_gfab253-B14","doi-asserted-by":"crossref","first-page":"11.10.1","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline","volume":"43","author":"Van der Auwera","year":"2013","journal-title":"Curr Protoc Bioinformatics"},{"key":"2022121608271746800_gfab253-B15","doi-asserted-by":"crossref","first-page":"412","DOI":"10.1038\/364412a0","article-title":"Co-crystal structure of the HNF-3\/fork head DNA-recognition motif resembles histone H5","volume":"364","author":"Clark","year":"1993","journal-title":"Nature"},{"key":"2022121608271746800_gfab253-B16","doi-asserted-by":"crossref","first-page":"e3000152","DOI":"10.1371\/journal.pbio.3000152","article-title":"Single-cell transcriptomics reveals gene expression dynamics of human fetal kidney development","volume":"17","author":"Hochane","year":"2019","journal-title":"PLoS Biol"},{"key":"2022121608271746800_gfab253-B17","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1002\/humu.22786","article-title":"Heterozygous deletion of FOXA2 segregates with disease in a family with heterotaxy, panhypopituitarism, and biliary atresia","volume":"36","author":"Tsai","year":"2015","journal-title":"Hum Mutat"},{"key":"2022121608271746800_gfab253-B18","doi-asserted-by":"crossref","first-page":"101705","DOI":"10.1016\/j.scr.2020.101705","article-title":"Generation of a human induced pluripotent stem cell line (QBRIi009-A) from a patient with a heterozygous deletion of FOXA2","volume":"42","author":"Elsayed","year":"2020","journal-title":"Stem Cell Res"},{"key":"2022121608271746800_gfab253-B19","doi-asserted-by":"crossref","first-page":"4315","DOI":"10.1093\/hmg\/ddx318","article-title":"Novel FOXA2 mutation causes hyperinsulinism, hypopituitarism with craniofacial and endoderm-derived organ abnormalities","volume":"26","author":"Giri","year":"2017","journal-title":"Hum Mol Genet"},{"key":"2022121608271746800_gfab253-B20","doi-asserted-by":"crossref","first-page":"1042","DOI":"10.1210\/jc.2017-02157","article-title":"Congenital hyperinsulinism and hypopituitarism attributable to a mutation in FOXA2","volume":"103","author":"Vajravelu","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"2022121608271746800_gfab253-B21","doi-asserted-by":"crossref","first-page":"103570","DOI":"10.1016\/j.ejmg.2018.11.004","article-title":"FOXA2 gene mutation in a patient with congenital complex pituitary hormone deficiency","volume":"62","author":"Boda","year":"2019","journal-title":"Eur J Med Genet"},{"key":"2022121608271746800_gfab253-B22","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1111\/pedi.12814","article-title":"Exome sequencing identifies a de novo FOXA2 variant in a patient with syndromic diabetes","volume":"20","author":"Stekelenburg","year":"2019","journal-title":"Pediatr Diabetes"},{"key":"2022121608271746800_gfab253-B23","doi-asserted-by":"crossref","first-page":"103668","DOI":"10.1016\/j.ejmg.2019.05.007","article-title":"Screening of a large cohort of blepharophimosis, ptosis, and epicanthus inversus syndrome patients reveals a very strong paternal inheritance bias and a wide spectrum of novel FOXL2 mutations","volume":"62","author":"Bunyan","year":"2019","journal-title":"Eur J Med Genet"},{"key":"2022121608271746800_gfab253-B24","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.ejmg.2014.08.004","article-title":"Co-occurrence of congenital hydronephrosis and FOXL2-associated blepharophimosis, ptosis, epicanthus inversus syndrome (BPES)","volume":"57","author":"Gulati","year":"2014","journal-title":"Eur J Med Genet"},{"key":"2022121608271746800_gfab253-B25","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/0092-8674(94)90523-1","article-title":"The winged-helix transcription factor HNF-3 beta is required for notochord development in the mouse embryo","volume":"78","author":"Weinstein","year":"1994","journal-title":"Cell"},{"key":"2022121608271746800_gfab253-B26","doi-asserted-by":"crossref","first-page":"13809","DOI":"10.1074\/jbc.M414122200","article-title":"Compensatory roles of Foxa1 and Foxa2 during lung morphogenesis","volume":"280","author":"Wan","year":"2005","journal-title":"J Biol Chem"},{"key":"2022121608271746800_gfab253-B27","doi-asserted-by":"crossref","first-page":"3435","DOI":"10.1101\/gad.1752608","article-title":"Dynamic regulation of Pdx1 enhancers by Foxa1 and Foxa2 is essential for pancreas development","volume":"22","author":"Gao","year":"2008","journal-title":"Genes Dev"},{"key":"2022121608271746800_gfab253-B28","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1038\/nature03649","article-title":"The initiation of liver development is dependent on Foxa transcription factors","volume":"435","author":"Lee","year":"2005","journal-title":"Nature"},{"key":"2022121608271746800_gfab253-B29","doi-asserted-by":"crossref","first-page":"596","DOI":"10.1002\/dvg.22404","article-title":"Foxa2-venus fusion reporter mouse line allows live-cell analysis of endoderm-derived organ formation","volume":"51","author":"Burtscher","year":"2013","journal-title":"Genesis"},{"key":"2022121608271746800_gfab253-B30","doi-asserted-by":"crossref","first-page":"1184","DOI":"10.1093\/nar\/23.7.1184","article-title":"Analysis of hepatocyte nuclear factor-3 beta protein domains required for transcriptional activation and nuclear targeting","volume":"23","author":"Qian","year":"1995","journal-title":"Nucleic Acids Res"},{"key":"2022121608271746800_gfab253-B31","doi-asserted-by":"crossref","first-page":"881","DOI":"10.1136\/bjo.2009.177972","article-title":"Mutation spectrum of fork-head transcriptional factor gene (FOXL2) in Indian Blepharophimosis Ptosis Epicanthus Inversus Syndrome (BPES) patients","volume":"95","author":"Kaur","year":"2011","journal-title":"Br J Ophthalmol"},{"key":"2022121608271746800_gfab253-B32","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1007\/s00439-006-0276-0","article-title":"A novel polyalanine expansion in FOXL2: the first evidence for a recessive form of the blepharophimosis syndrome (BPES) associated with ovarian dysfunction","volume":"121","author":"Nallathambi","year":"2007","journal-title":"Hum Genet"},{"key":"2022121608271746800_gfab253-B33","doi-asserted-by":"crossref","first-page":"9069","DOI":"10.1093\/nar\/gkz627","article-title":"Pre-marked chromatin and transcription factor co-binding shape the pioneering activity of Foxa2","volume":"47","author":"Cernilogar","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2022121608271746800_gfab253-B34","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.molcel.2016.03.001","article-title":"The pioneer transcription factor FoxA maintains an accessible nucleosome configuration at enhancers for tissue-specific gene activation","volume":"62","author":"Iwafuchi-Doi","year":"2016","journal-title":"Mol Cell"},{"key":"2022121608271746800_gfab253-B35","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1007\/978-1-4939-9631-5_9","article-title":"Differentiation of urothelium from mouse embryonic stem cells in chemically defined conditions","volume":"2029","author":"Boumelhem","year":"2019","journal-title":"Methods Mol Biol"},{"key":"2022121608271746800_gfab253-B36","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.ydbio.2007.01.010","article-title":"Directed differentiation of embryonic stem cells into bladder tissue","volume":"304","author":"Oottamasathien","year":"2007","journal-title":"Dev Biol"},{"key":"2022121608271746800_gfab253-B37","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1242\/dev.117903","article-title":"An illustrated anatomical ontology of the developing mouse lower urogenital tract","volume":"142","author":"Georgas","year":"2015","journal-title":"Development"},{"key":"2022121608271746800_gfab253-B38","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1038\/35019088","article-title":"GATA3 haplo-insufficiency causes human HDR syndrome","volume":"406","author":"Van Esch","year":"2000","journal-title":"Nature"},{"key":"2022121608271746800_gfab253-B39","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1002\/humu.21378","article-title":"Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract","volume":"31","author":"Gimelli","year":"2010","journal-title":"Hum Mutat"},{"key":"2022121608271746800_gfab253-B40","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1016\/j.stem.2011.01.017","article-title":"Targeting SOX17 in human embryonic stem cells creates unique strategies for isolating and analyzing developing endoderm","volume":"8","author":"Wang","year":"2011","journal-title":"Cell Stem Cell"},{"key":"2022121608271746800_gfab253-B41","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.celrep.2019.03.076","article-title":"Single-cell RNA-sequencing-based CRISPRi screening resolves molecular drivers of early human endoderm development","volume":"27","author":"Genga","year":"2019","journal-title":"Cell Rep"}],"container-title":["Nephrology Dialysis Transplantation"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/ndt\/advance-article-pdf\/doi\/10.1093\/ndt\/gfab253\/40520997\/gfab253.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/37\/10\/1833\/47998134\/gfab253.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/ndt\/article-pdf\/37\/10\/1833\/47998134\/gfab253.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,8]],"date-time":"2023-01-08T14:04:17Z","timestamp":1673186657000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/ndt\/article\/37\/10\/1833\/6362937"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,2]]},"references-count":41,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,9,2]]},"published-print":{"date-parts":[[2022,9,22]]}},"URL":"https:\/\/doi.org\/10.1093\/ndt\/gfab253","relation":{},"ISSN":["0931-0509","1460-2385"],"issn-type":[{"value":"0931-0509","type":"print"},{"value":"1460-2385","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2022,10]]},"published":{"date-parts":[[2021,9,2]]}}}