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

TitleNovel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.
Publication TypeJournal Article
Year of Publication2016
AuthorsOckeloen, CW, Khandelwal, KD, Dreesen, K, Ludwig, KU, Sullivan, R, van Rooij, IALM, Thonissen, M, Swinnen, S, Phan, M, Conte, F, Ishorst, N, Gilissen, C, RoaFuentes, L, van de Vorst, M, Henkes, A, Steehouwer, M, van Beusekom, E, Bloemen, M, Vankeirsbilck, B, Bergé, S, Hens, G, Schoenaers, J, Poorten, VVander, Roosenboom, J, Verdonck, A, Devriendt, K, Roeleveldt, N, Jhangiani, SN, Vissers, LELM, Lupski, JR, de Ligt, J, Hoff, JWVon den, Pfundt, R, Brunner, HG, Zhou, H, Dixon, J, Mangold, E, van Bokhoven, H, Dixon, MJ, Kleefstra, T, Hoischen, A, Carels, CEL
JournalGenet Med
Date Published2016 Nov
KeywordsAdolescent, Anodontia, Child, Exome, Female, Frameshift Mutation, Genetic Predisposition to Disease, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Male, Mutation, Missense, Pedigree, Sequence Analysis, DNA, Wnt Signaling Pathway

PURPOSE: 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.METHODS: 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.RESULTS: 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.CONCLUSION: Mutations in LRP6 cause TA in humans.Genet Med 18 11, 1158-1162.

Alternate JournalGenet Med
PubMed ID26963285
PubMed Central IDPMC5018235
Grant ListG0901539 / MRC_ / Medical Research Council / United Kingdom
U54 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
MR/M012174/1 / MRC_ / Medical Research Council / United Kingdom
R01 NS058529 / NS / NINDS NIH HHS / United States

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