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Genet Med. 2016 Nov;18(11):1158-1162. doi: 10.1038/gim.2016.10. Epub 2016 Mar 10.

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

Author information

1
Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
2
Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
3
Department of Oral Health Sciences, University Hospitals KU Leuven, 3000, Leuven, Belgium.
4
Institute of Human Genetics, Department of Genomics, Life & Brain Center, University of Bonn, D-53127, Bonn, Germany.
5
Faculty of Life Sciences and Dental School, University of Manchester, M13 9PT, Manchester, United Kingdom.
6
Department for Health Evidence, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
7
Radboud University, Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, 6500 HB, Nijmegen, The Netherlands.
8
DNA facility, Center for Human Genetics, University Hospitals KU Leuven, 3000, Leuven, Belgium.
9
Department of Oral and Maxillofacial Surgery, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
10
Cleft Lip Palate Team and AGORA-Support Group, Departments of Otorhinolaryngology and Head and Neck Surgery, Maxillofacial Surgery, and Orthodontics, University Hospitals KU Leuven, 3000, Leuven, Belgium.
11
Center for Human Genetics, Department of Clinical Genetics, University Hospitals KU Leuven, 3000, Leuven, Belgium.
12
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, Texas, USA.
13
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, Texas, USA.
14
Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, Texas, USA.
15
Texas Children's Hospital, Houston, TX 77030, Texas, USA.
16
Hubrecht Institute, KNAW and University Medical Center Utrecht, 3508 AD, Utrecht, The Netherlands.
17
Institute of Human Genetics, Biomedical Center, University of Bonn, D-53127, Bonn, Germany.
18
Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
#
Contributed equally

Abstract

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.

PMID:
26963285
PMCID:
PMC5018235
DOI:
10.1038/gim.2016.10
[Indexed for MEDLINE]
Free PMC Article

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