Title :

Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling.

Author(s) :

Dufour, William [Auteur]
Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 [RADEME]
Alawbathani, S. [Auteur]
Jourdain, Anne-Sophie [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Asif, M. [Auteur]
Baujat, G. [Auteur]
Becker, C. [Auteur]
Budde, B. [Auteur]
Gallacher, L. [Auteur]
Georgomanolis, T. [Auteur]
Ghoumid, Jamal [Auteur]
Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 [RADEME]
Höhne, W. [Auteur]
Lyonnet, S. [Auteur]
Ba-Saddik, I. A. [Auteur]
Manouvrier-Hanu, S. [Auteur]
Motameny, S. [Auteur]
Noegel, A. A. [Auteur]
Pais, L. [Auteur]
Vanlerberghe, Clemence [Auteur]
Maladies RAres du DEveloppement embryonnaire et du MEtabolisme : du Phénotype au Génotype et à la Fonction - ULR 7364 [RADEME]
Wagle, P. [Auteur]
White, S. M. [Auteur]
Willems, M. [Auteur]
Nürnberg, P. [Auteur]
Narducci, Fabienne [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Petit, Florence [Auteur]
Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364
Hussain, Muhammad Sajid [Auteur]
University Hospital of Cologne [Cologne]

Journal title :

Genetics in Medicine

Abbreviated title :

Genet Med

Volume number :

24

Pages :

1708-1721

Publisher :

American College of Medical Genetics and Genomics

Publication date :

2022-05-26

ISSN :

1530-0366

English keyword(s) :

WNT signaling
Limb malformation
LEF1
Ectodermal dysplasia

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Purpose LEF1 encodes a transcription factor acting downstream of the WNT-β-catenin signaling pathway. It was recently suspected as a candidate for ectodermal dysplasia in 2 individuals carrying 4q35 microdeletions. We ...
Show more >Purpose LEF1 encodes a transcription factor acting downstream of the WNT-β-catenin signaling pathway. It was recently suspected as a candidate for ectodermal dysplasia in 2 individuals carrying 4q35 microdeletions. We report on 12 individuals harboring LEF1 variants. Methods High-throughput sequencing was employed to delineate the genetic underpinnings of the disease. Cellular consequences were characterized by immunofluorescence, immunoblotting, pulldown assays, and/or RNA sequencing. Results Monoallelic variants in LEF1 were detected in 11 affected individuals from 4 unrelated families, and a biallelic variant was detected in an affected individual from a consanguineous family. The phenotypic spectrum includes various limb malformations, such as radial ray defects, polydactyly or split hand/foot, and ectodermal dysplasia. Depending on the type and location of LEF1 variants, the inheritance of this novel Mendelian condition can be either autosomal dominant or recessive. Our functional data indicate that 2 molecular mechanisms are at play: haploinsufficiency or loss of DNA binding are responsible for a mild to moderate phenotype, whereas loss of β-catenin binding caused by biallelic variants is associated with a severe phenotype. Transcriptomic studies reveal an alteration of WNT signaling. Conclusion Our findings establish mono- and biallelic variants in LEF1 as a cause for a novel syndrome comprising limb malformations and ectodermal dysplasia.Show less >

Language :

Anglais

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

Université de Lille
CHU Lille

Collections :

• Maladies Rares du Développement : Génétique, Régulation et Protéomique (RADEME) - ULR 7364

Submission date :

2023-06-05T07:03:42Z
2024-06-19T08:16:34Z
2024-07-05T09:30:07Z