The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene

Servi J.C. Stevens*, Constance T.R.M. Stumpel, Karin E.M. Diderich, Marjon A. van Slegtenhorst, Mary Alice Abbott, Courtney Manning, Jorune Balciuniene, Louise C. Pyle, Jacqueline Leonard, Jill R. Murrell, Romy van de Putte, Iris A.L.M. van Rooij, Alexander Hoischen, Paul Lasko, Han G. Brunner

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals.

Original languageEnglish
Pages (from-to)183-189
Number of pages7
JournalClinical Genetics
Volume101
Issue number2
Early online date20 Oct 2021
DOIs
Publication statusPublished - Feb 2022

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© 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.

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