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 Pathologique [CHU Clermont-Ferrand]
4 UNIL - Université de Lausanne = University of 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]

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: Sirenomelia; exome sequencing; CDX2 de novo mutation; audal dysgenesis

Domains: Life Sciences [q-bio]

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⟩