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Exome sequencing identifies the first genetic determinants of sirenomelia in humans

François Lecoquierre 1 Anne‐claire Brehin 1 Sophie Coutant 1 Juliette Coursimault 1 Anne Bazin 2 Wilfrid Finck 3 Guillaume Benoist 4 Marianne Begorre 5 Claire Beneteau 6 Daniel Cailliez 7 Pierre Chenal 7 Mirjam de Jong 8 Sophie Degré 7 Louise Devisme 9 Christine Francannet 10 Bénédicte Gérard 11 Corinne Jeanne 12 Madeleine Joubert 12 Hubert Journel 13 Hélène Laurichesse Delmas 10 Valérie Layet 14 Alain Liquier Raphaele Mangione Sophie Patrier 15 Fanny Pelluard 16 Florence Petit 17 Nadia Tillouche Conny Ravenswaaij‐arts Thierry Frebourg 1 Pascale Saugier‐veber 1 Nicolas Gruchy 18 Gaël Nicolas 19, 1 Marion Gerard 20 
Abstract : 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.
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Submitted on : Thursday, April 9, 2020 - 12:07:19 PM
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François Lecoquierre, Anne‐claire Brehin, Sophie Coutant, Juliette Coursimault, Anne Bazin, et al.. Exome sequencing identifies the first genetic determinants of sirenomelia in humans. Human Mutation, Wiley, 2020, 41 (5), pp.926-933. ⟨10.1002/humu.23998⟩. ⟨hal-02538246⟩



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