Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Lecoquierre, F., Brehin, A-C., Coutant, S., Coursimault, J., Bazin, A., Finck, W., Benoist, G., Begorre, M., Beneteau, C., Cailliez, D., Chenal, P., De Jong, M., Degre, S., Devisme, L., Francannet, C., Gerard, B., Jeanne, C., Joubert, M., Journel, H., Laurichesse Delmas, H., Layet, V., Liquier, A., Mangione, R., Patrier, S., Pelluard, F., Petit, F., Tillouche, N., Van Ravenswaaij-Arts, C., Frebourg, T., Saugier-Veber, P., Gruchy, N., Nicolas, G. & Gerard, M., May-2020, In : Human Mutation. 41, 5, p. 926-933 8 p.

Research output: Contribution to journalArticleAcademicpeer-review

Copy link to clipboard


  • Exome sequencing identifies the first genetic determinants of sirenomelia in humans

    Final publisher's version, 1.5 MB, PDF document

    Request copy


  • 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 Delmas
  • Valerie 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

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, CAUDAL REGRESSION, DEFECTS, REQUIREMENT, GROWTH

ID: 133421242