Monoallelic and biallelic variants in LEF1 are associated with a new syndrome combining ectodermal dysplasia and limb malformations caused by altered WNT signaling
Open accessAbstract
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.
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Some genes (TRAF6, LEF1, LRP6) have not yet been assigned to ED in the OMIM compendium.
“However, some of these genes have not yet been assigned to ED in the OMIM compendium, i.e., TRAF6 [11,12], LEF1 [13,14], or LRP6 [15].”
From Molecular Pathway-Based Classification of Ectodermal Dysplasias: First Five-Yearly Update (2022) · cites this paper as [14]
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- Authors
- Dufour, W., Alawbathani, S., Jourdain, A.-S., Asif, M., Baujat, G., Becker, C., Budde, B., Gallacher, L., Georgomanolis, T., Ghoumid, J., Höhne, W., Lyonnet, S., Ba-Saddik, I. A., Manouvrier-Hanu, S., Motameny, S., Noegel, A. A., Pais, L., Vanlerberghe, C., Wagle, P., White, S. M., Willems, M., Nürnberg, P., Escande, F., Petit, F., & Hussain, M. S.
- Affiliations
- Université de Lille (FR)
- University of Cologne (DE)
- Hôpital Necker-Enfants Malades (FR)
- The University of Melbourne (AU)
- University of Aden (YE)
- Broad Institute (US)
- Hôpital Arnaud de Villeneuve (FR)
- Corresponding author
- Petit, Florence
- Hussain, Muhammad Sajid
- ORCID
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2022-08
- Volume
- 24
- Issue
- 8
- Pages
- 1708-1721
- ISSN
- 1098-3600 (ISSN-L)
- OpenAlex
- W4280546381
- Cited by
- 14
- References
- 35
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 3 · 2023: 1 · 2022: 3
- FWCI
- 2.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genetics in Medicine (publishedVersion)
- PubMed (publishedVersion)
- Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
- HAL (submittedVersion)
- LillOA (Université de Lille (University Of Lille)) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › dental development and anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Keywords
- LEF1, Wnt/β-catenin signaling, ectodermal dysplasia, limb malformations, monoallelic variants, biallelic variants, radial ray defects, polydactyly, haploinsufficiency, autosomal dominant inheritance, autosomal recessive inheritance, consanguineous family, new syndrome
- MeSH terms
- Consanguinity, Ectodermal Dysplasia, Humans, Syndrome, Limb Deformities, Congenital, beta Catenin, Lymphoid Enhancer-Binding Factor 1, Wnt Signaling Pathway
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