Dufour, William, Alawbathani, Salem, Jourdain, Anne-Sophie, Asif, Maria, Baujat, Genevieve, Becker, Christian, Budde, Birgit, Gallacher, Lyndon, Georgomanolis, Theodoros, Ghoumid, Jamal, Hoehne, Wolfgang, Lyonnet, Stanislas, Ba-Saddik, Iman Ali, Manouvrier-Hanu, Sylvie, Motameny, Susanne, Noegel, Angelika A., Pais, Lynn, Vanlerberghe, Clemence, Wagle, Prerana, White, Susan M., Willems, Marjolaine, Nuernberg, Peter, Escande, Fabienne, Petit, Florence and Hussain, Muhammad Sajid ORCID: 0000-0002-1353-8809 (2022). Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling. Genet. Med., 24 (8). S. 1708 - 1722. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1530-0366

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Abstract

Purpose: LEF1 encodes a transcription factor acting downstream of the WNT-beta-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 beta-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. (C) 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Dufour, WilliamUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Alawbathani, SalemUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jourdain, Anne-SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Asif, MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Baujat, GenevieveUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Budde, BirgitUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gallacher, LyndonUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Georgomanolis, TheodorosUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ghoumid, JamalUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, WolfgangUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lyonnet, StanislasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ba-Saddik, Iman AliUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Manouvrier-Hanu, SylvieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Motameny, SusanneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noegel, Angelika A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pais, LynnUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Vanlerberghe, ClemenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wagle, PreranaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
White, Susan M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Willems, MarjolaineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Escande, FabienneUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Petit, FlorenceUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hussain, Muhammad SajidUNSPECIFIEDorcid.org/0000-0002-1353-8809UNSPECIFIED
URN: urn:nbn:de:hbz:38-693353
DOI: 10.1016/j.gim.2022.04.022
Journal or Publication Title: Genet. Med.
Volume: 24
Number: 8
Page Range: S. 1708 - 1722
Date: 2022
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1530-0366
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENE; MUTATIONS; DNA; EXPRESSION; INITIATION; PHENOTYPE; CHROMATIN; COMPLEX; DOMAIN; HOXD13Multiple languages
Genetics & HeredityMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/69335

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