De novo mutations in Caudal Type Homeo Box transcription Factor 2 (CDX2) in patients with persistent cloaca

Jacob S.J. Hsu, Manting So, Clara S.M. Tang, Anwarul Karim, Robert M. Porsch, Carol Wong, Michelle Yu, Fanny Yeung, Huimin Xia, Ruizhong Zhang, Stacey S. Cherny, Patrick H.Y. Chung, Kenneth K.Y. Wong, Pak C. Sham, Ngoc Diem Ngo, Miaoxin Li, Paul K.H. Tam, Vincent C.H. Lui, Maria Mercè Garcia-Barcelo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


The cloaca is an embryonic cavity that is divided into the urogenital sinus and rectum upon differentiation of the cloacal epithelium triggered by tissue-specific transcription factors including CDX2. Defective differentiation leads to persistent cloaca in humans (PC), a phenotype recapitulated in Cdx2 mutant mice. PC is linked to hypo/hyper-vitaminosis A. Although no gene has ever been identified, there is a strong evidence for a genetic contribution to PC. We applied whole-exome sequencing and copy-number-variants analyses to 21 PC patients and their unaffected parents. The damaging p.Cys132* and p.Arg237His de novo CDX2 variants were identified in two patients. These variants altered the expression of CYP26A1, a direct CDX2 target encoding the major retinoic acid (RA)-degrading enzyme. Other RA genes, including the RA-receptor alpha, were also mutated. Genes governing the development of cloaca-derived structures were recurrently mutated and over-represented in the basement-membrane components set (q-value < 1.65×10-6). Joint analysis of the patients' profile highlighted the extracellular matrix-receptor interaction pathway (MsigDBID: M7098, FDR: q-value<7.16×10-9). This is the first evidence that PC is genetic, with genes involved in the RA metabolismat the lead. Given the CDX2 de novo variants and the role of RA, our observations could potentiate preventive measures. For the first time, a gene recapitulating PC in mouse models is found mutated in humans.

Original languageEnglish
Pages (from-to)351-358
Number of pages8
JournalHuman Molecular Genetics
Issue number2
StatePublished - 15 Jan 2018
Externally publishedYes


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