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

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

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1158-1162
Number of pages5
JournalGenetics in Medicine
Issue number11
Publication statusPublished - Nov 2016


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