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Article Dans Une Revue Human Mutation Année : 2020

Exome sequencing identifies the first genetic determinants of sirenomelia in humans

Louise Devisme
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Christine Francannet
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Corinne Jeanne
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Madeleine Joubert
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Alain Liquier
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Raphaele Mangione
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Florence Petit
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Nadia Tillouche
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Conny Ravenswaaij‐arts
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Marion Gerard
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Résumé

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.

Dates et versions

hal-02538246 , version 1 (09-04-2020)

Identifiants

Citer

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, 2020, 41 (5), pp.926-933. ⟨10.1002/humu.23998⟩. ⟨hal-02538246⟩
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