title: Novel mutations in LRP6 highlight the role of WNT signaling in tooth agenesis.
abstract: 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 Med 18 11, 1158-1162.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Charlotte W
authors.initials: CW
authors.lastname: Ockeloen
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Kriti D
authors.initials: KD
authors.lastname: Khandelwal
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.|Department of Oral Health Sciences, University Hospitals KU Leuven, 3000, Leuven, Belgium.
authors.forename: Karoline
authors.initials: K
authors.lastname: Dreesen
authors.affiliation: Institute of Human Genetics, Department of Genomics, Life & Brain Center, University of Bonn, D-53127, Bonn, Germany.
authors.forename: Kerstin U
authors.initials: KU
authors.lastname: Ludwig
authors.affiliation: Faculty of Life Sciences and Dental School, University of Manchester, M13 9PT, Manchester, United Kingdom.
authors.forename: Robert
authors.initials: R
authors.lastname: Sullivan
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Iris A L M
authors.initials: IALM
authors.lastname: van Rooij
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Michelle
authors.initials: M
authors.lastname: Thonissen
authors.affiliation: Department of Oral Health Sciences, University Hospitals KU Leuven, 3000, Leuven, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Swinnen
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Milien
authors.initials: M
authors.lastname: Phan
authors.affiliation: Radboud University, Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Federica
authors.initials: F
authors.lastname: Conte
authors.affiliation: Institute of Human Genetics, Department of Genomics, Life & Brain Center, University of Bonn, D-53127, Bonn, Germany.
authors.forename: Nina
authors.initials: N
authors.lastname: Ishorst
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Laury
authors.initials: L
authors.lastname: RoaFuentes
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Maartje
authors.initials: M
authors.lastname: van de Vorst
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Arjen
authors.initials: A
authors.lastname: Henkes
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: Steehouwer
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: van Beusekom
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Marjon
authors.initials: M
authors.lastname: Bloemen
authors.affiliation: DNA facility, Center for Human Genetics, University Hospitals KU Leuven, 3000, Leuven, Belgium.
authors.forename: Bruno
authors.initials: B
authors.lastname: Vankeirsbilck
authors.affiliation: Department of Oral and Maxillofacial Surgery, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Stefaan
authors.initials: S
authors.lastname: Bergé
authors.affiliation: 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.
authors.forename: Greet
authors.initials: G
authors.lastname: Hens
authors.affiliation: 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.
authors.forename: Joseph
authors.initials: J
authors.lastname: Schoenaers
authors.affiliation: 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.
authors.forename: Vincent Vander
authors.initials: VV
authors.lastname: Poorten
authors.affiliation: 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.
authors.forename: Jasmien
authors.initials: J
authors.lastname: Roosenboom
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.|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.
authors.forename: An
authors.initials: A
authors.lastname: Verdonck
authors.affiliation: 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.|Center for Human Genetics, Department of Clinical Genetics, University Hospitals KU Leuven, 3000, Leuven, Belgium.
authors.forename: Koen
authors.initials: K
authors.lastname: Devriendt
authors.affiliation: Department for Health Evidence, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Nel
authors.initials: N
authors.lastname: Roeleveldt
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, Texas, USA.
authors.forename: Shalini N
authors.initials: SN
authors.lastname: Jhangiani
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Lisenka E L M
authors.initials: LELM
authors.lastname: Vissers
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, Texas, USA.|Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, Texas, USA.|Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, Texas, USA.|Texas Children's Hospital, Houston, TX 77030, Texas, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Lupski
authors.affiliation: Hubrecht Institute, KNAW and University Medical Center Utrecht, 3508 AD, Utrecht, The Netherlands.
authors.forename: Joep
authors.initials: J
authors.lastname: de Ligt
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Johannes W
authors.initials: JW
authors.lastname: Von den Hoff
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Rolph
authors.initials: R
authors.lastname: Pfundt
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.|Radboud University, Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Huiqing
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Faculty of Life Sciences and Dental School, University of Manchester, M13 9PT, Manchester, United Kingdom.
authors.forename: Jill
authors.initials: J
authors.lastname: Dixon
authors.affiliation: Institute of Human Genetics, Biomedical Center, University of Bonn, D-53127, Bonn, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Mangold
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.|Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Faculty of Life Sciences and Dental School, University of Manchester, M13 9PT, Manchester, United Kingdom.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dixon
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.|Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.|Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, 6500 HB, Nijmegen, The Netherlands.|Department of Oral Health Sciences, University Hospitals KU Leuven, 3000, Leuven, Belgium.
authors.forename: Carine E L
authors.initials: CEL
authors.lastname: Carels
mesh_terms: D000293:Adolescent; D000848:Anodontia / Q000235:genetics* / Q000473:pathology; D002648:Child; D059472:Exome / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation / Q000235:genetics; D020022:Genetic Predisposition to Disease; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010375:Pedigree; D017422:Sequence Analysis, DNA; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6