The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene.
| Title: | The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene. |
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| Authors: | Stevens SJC; Department of Clinical Genetics, Maastricht University Medical Centre and GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.; Stumpel CTRM; Department of Clinical Genetics, Maastricht University Medical Centre and GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.; Diderich KEM; Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.; van Slegtenhorst MA; Department of Clinical Genetics, Erasmus Medical Centre, Rotterdam, the Netherlands.; Abbott MA; Department of Pediatrics, University of Massachusetts Medical School-Baystate, Springfield, Massachusetts, USA.; Manning C; Department of Pediatrics, University of Massachusetts Medical School-Baystate, Springfield, Massachusetts, USA.; Balciuniene J; Division of Human Genetics and the Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Pyle LC; Division of Human Genetics and the Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Leonard J; Division of Human Genetics and the Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; Murrell JR; Division of Human Genetics and the Roberts Individualized Medical Genetics Center, Children's Hospital of Philadelphia, Philadelphia, PA, USA.; van de Putte R; Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; van Rooij IALM; Department for Health Evidence, Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.; Hoischen A; Department of Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.; Lasko P; Department of Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.; Department of Biology, McGill University, Montréal, Québec, Canada.; Brunner HG; Department of Clinical Genetics, Maastricht University Medical Centre and GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands.; Department of Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands. |
| Source: | Clinical genetics [Clin Genet] 2022 Feb; Vol. 101 (2), pp. 183-189. Date of Electronic Publication: 2021 Oct 28. |
| Publication Type: | Case Reports; Journal Article |
| Language: | English |
| Journal Info: | Publisher: Munksgaard Country of Publication: Denmark NLM ID: 0253664 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1399-0004 (Electronic) Linking ISSN: 00099163 NLM ISO Abbreviation: Clin Genet Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Copenhagen, Munksgaard. |
| MeSH Terms: | Genetic Predisposition to Disease* ; Mutation* ; Phenotype*; Abnormalities, Multiple/*diagnosis ; Abnormalities, Multiple/*genetics ; CDX2 Transcription Factor/*genetics ; Sacrococcygeal Region/*abnormalities; Alleles ; Child ; Female ; Genetic Association Studies ; Genetic Testing ; Genotype ; Humans ; Infant ; Infant, Newborn ; Male ; Exome Sequencing |
| 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.; (© 2021 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.) |
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| Grant Information: | K08 CA248704 United States CA NCI NIH HHS; KL2 TR001879 United States TR NCATS NIH HHS; T32 GM008638 United States GM NIGMS NIH HHS |
| Contributed Indexing: | Keywords: CDX2; VACTERL; caudal regression syndrome; homeobox gene; imperforate anus; persistent cloaca; sirenomelia |
| Substance Nomenclature: | 0 (CDX2 Transcription Factor); 0 (CDX2 protein, human) |
| Entry Date(s): | Date Created: 20211021 Date Completed: 20220328 Latest Revision: 20221207 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9153267 |
| DOI: | 10.1111/cge.14076 |
| PMID: | 34671974 |
| Database: | MEDLINE |
Case Reports; Journal Article