|Title||Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Ockeloen, 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|
|Date Published||2016 11|
|Keywords||Adolescent, 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 Journal||Genet. Med.|
|PubMed Central ID||PMC5018235|
|Grant List||U54 HG006542 / HG / NHGRI NIH HHS / United States |
MR/M012174/1 / / Medical Research Council / United Kingdom
UM1 HG006542 / HG / NHGRI NIH HHS / United States
G0901539 / / Medical Research Council / United Kingdom
R01 NS058529 / NS / NINDS NIH HHS / United States