Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Francois Lecoquierre, Anne-Claire Brehin, Sophie Coutant, Juliette Coursimault, Anne Bazin, Wilfrid Finck, Guillaume Benoist, Marianne Begorre, Claire Beneteau, Daniel Cailliez, Pierre Chenal, Mirjam De Jong, Sophie Degre, Louise Devisme, Christine Francannet, Benedicte Gerard, Corinne Jeanne, Madeleine Joubert, Hubert Journel, Helene Laurichesse DelmasValerie Layet, Alain Liquier, Raphaele Mangione, Sophie Patrier, Fanny Pelluard, Florence Petit, Nadia Tillouche, Conny Van Ravenswaaij-Arts, Thierry Frebourg, Pascale Saugier-Veber, Nicolas Gruchy, Gael Nicolas, Marion Gerard

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)


Sirenomelia is a rare severe malformation sequence of unknown cause characterized by fused legs and severe visceral abnormalities. We present a series of nine families including two rare familial aggregations of sirenomelia investigated by a trio-based exome sequencing strategy. This approach identified CDX2 variants in the two familial aggregations, both fitting an autosomal dominant pattern of inheritance with variable expressivity. CDX2 is a major regulator of caudal development in vertebrate and mouse heterozygotes are a previously described model of sirenomelia. Remarkably, the p.(Arg237His) variant has already been reported in a patient with persistent cloaca. Analysis of the sporadic cases revealed six additional candidate variants including a de novo frameshift variant in the genetically constrained NKD1 gene, encoding a known interactor of CDX2. We provide the first insights for a genetic contribution in human sirenomelia and highlight the role of Cdx and Wnt signaling pathways in the development of this disorder.

Original languageEnglish
Pages (from-to)926-933
Number of pages8
JournalHuman Mutation
Issue number5
Publication statusPublished - May-2020


  • caudal dysgenesis
  • CDX2
  • de novo mutation
  • exome sequencing
  • Sirenomelia

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