Journal Article

Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis

Verdonck, An, Zhou, Huiqing, Hoischen, Alexander, Vissers, Lisenka E.L.M., Dixon, Michael J., Bergé, Stefaan, Thonissen, Michelle, van Rooij, Iris A.L.M., Roeleveldt, Nel, Schoenaers, Joseph, van de Vorst, Maartje, Vankeirsbilck, Bruno, Jhangiani, Shalini N., Phan, Milien, Roosenboom, Jasmien, Lupski, James R., Carels, Carine E.L., Dixon, Jill, Brunner, Han G., Mangold, Elisabeth, Kleefstra, Tjitske, Ockeloen, Charlotte W., Henkes, Arjen, Pfundt, Rolph, Bloemen, Marjon, Conte, Federica, Steehouwer, Marloes, Khandelwal, Kriti D., Roa Fuentes, Laury, de Ligt, Joep, Sullivan, Robert, Von den Hoff, Johannes W., Ludwig, Kerstin U., Gilissen, Christian, Hens, Greet, van Beusekom, Ellen, van Bokhoven, Hans, Swinnen, Steven, Vander Poorten, Vincent, Devriendt, Koen, Dreesen, Karoline, Ishorst, Nina

2016

Overview

We aimed to identify a novel genetic cause of tooth agenesis (TA) and/or orofacial clefting (OFC) by combining whole-exome sequencing (WES) and targeted resequencing in a large cohort of TA and OFC patients. WES was performed in two unrelated patients: one with severe TA and OFC and another with severe TA only. After deleterious mutations were identified in a gene encoding low-density lipoprotein receptor-related protein 6 (LRP6), all its exons were resequenced with molecular inversion probes in 67 patients with TA, 1,072 patients with OFC, and 706 controls. We identified a frameshift (c.4594delG, p.Cys1532fs) and a canonical splice-site mutation (c.3398-2A>C, p.?) in LRP6, respectively, in the patient with TA and OFC and in the patient with severe TA only. The targeted resequencing showed significant enrichment of unique LRP6 variants in TA patients but not in nonsyndromic OFC patients. Of the five variants in patients with TA, two affected the canonical splice site and three were missense variants; all variants segregated with the dominant phenotype, and in one case the missense mutation occurred de novo. Mutations in LRP6 cause TA in humans. Genet Med18 11, 1158–1162.

• Publisher: Elsevier Inc,Nature Publishing Group US,Elsevier Limited
• Subject: 631/80/86 / 692/420/2489/144 / 692/700/3032/3039 / 692/700/3032/3129/3133 / Adolescent / Anodontia - genetics / Anodontia - pathology / Biomedicine / brief-report / Child / Exome - genetics / Female / Frameshift Mutation - genetics / Genetic Predisposition to Disease / Human Genetics / Humans / Laboratory Medicine / Low Density Lipoprotein Receptor-Related Protein-6 - genetics / LRP6 / Male / molecular inversion probes / Mutation, Missense - genetics / Pedigree / Sequence Analysis, DNA / tooth agenesis / Wnt Signaling Pathway - genetics / Wnt/β-catenin canonical signaling pathway