Exome sequencing identifies the first genetic determinants of sirenomelia in humans. Issue 5 (1st March 2020)

• Record Type: Journal Article
• Authors: Lecoquierre, François; Brehin, Anne‐Claire; Coutant, Sophie; Coursimault, Juliette; Bazin, Anne; Finck, Wilfrid; Benoist, Guillaume; Begorre, Marianne; Beneteau, Claire; Cailliez, Daniel; Chenal, Pierre; De Jong, Mirjam; Degré, Sophie; Devisme, Louise; Francannet, Christine; Gérard, Bénédicte; Jeanne, Corinne; Joubert, Madeleine; Journel, Hubert; Laurichesse Delmas, Hélène; Layet, Valérie; Liquier, Alain; Mangione, Raphaele; Patrier, Sophie; Pelluard, Fanny; Petit, Florence; Tillouche, Nadia; van Ravenswaaij‐Arts, Conny; Frebourg, Thierry; Saugier‐Veber, Pascale; Gruchy, Nicolas; Nicolas, Gaël; Gerard, Marion;
• Is Part Of: Human mutation. Volume 41:Issue 5(2020)
• Page Start: 926
• Page End: 933
• Publication Date: 2020-03-01
• Subjects: caudal dysgenesis -- CDX2 -- de novo mutation -- exome sequencing -- Sirenomelia; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23998
• Languages: English
• ISSNs: 1059-7794

Abstract

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.