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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
1 GPMCND - Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques
2 Laboratoire CERBA [Saint Ouen l'Aumône]
3 Service d'anatomie et cytologie pathologiques (CHU Clermont Ferrand)
4 UNIL - Université de Lausanne
5 Service de Gynécologie-Obstétrique et Médecine de la Reproduction [CHU Caen]
6 Service de génétique médicale - Unité de génétique clinique [Nantes]
7 Groupe Hospitalier du Havre
8 University of Groningen [Groningen]
9 Institut de Pathologie [CHU Lille]
10 CHU Clermont-Ferrand
11 Service d'hématologie et immunologie
12 CHU Caen
13 Génétique Médicale
14 Unité de Cytogénétique et Génétique Médicale
15 Service d'Anatomie et Cytologie Pathologique [CHU Rouen]
16 Laboratoire d'anatomie pathologique
17 IMBE - Institut méditerranéen de biodiversité et d'écologie marine et continentale
18 Laboratoire de cytogénétique prénatale [CHU Caen]
19 UNIROUEN UFR Santé - UNIROUEN - UFR Santé
20 Service de Génétique [CHU Caen]
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.
Keywords : audal dysgenesis CDX2 de novo mutation exome sequencing Sirenomelia
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https://hal-normandie-univ.archives-ouvertes.fr/hal-02538246
Contributor : Nathalie Porchet <>
Submitted on : Thursday, April 9, 2020 - 12:07:19 PM
Last modification on : Friday, June 11, 2021 - 8:38:03 AM

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COMUE-NORMANDIE | UNIV-AVIGNON | UNIV-NANTES | IMBE | UNIROUEN | UNIV-AMU | UNICAEN | GPMCND | CNRS | OSU-INSTITUT-PYTHEAS | UNIV-PARIS

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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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