title: Tooth agenesis and orofacial clefting: genetic brothers in arms?
abstract: Tooth agenesis and orofacial clefts represent the most common developmental anomalies and their co-occurrence is often reported in patients as well in animal models. The aim of the present systematic review is to thoroughly investigate the current literature (PubMed, EMBASE) to identify the genes and genomic loci contributing to syndromic or non-syndromic co-occurrence of tooth agenesis and orofacial clefts, to gain insight into the molecular mechanisms underlying their dual involvement in the development of teeth and facial primordia. Altogether, 84 articles including phenotype and genotype description provided 9 genomic loci and 26 gene candidates underlying the co-occurrence of the two congenital defects: MSX1, PAX9, IRF6, TP63, KMT2D, KDM6A, SATB2, TBX22, TGFα, TGFβ3, TGFβR1, TGFβR2, FGF8, FGFR1, KISS1R, WNT3, WNT5A, CDH1, CHD7, AXIN2, TWIST1, BCOR, OFD1, PTCH1, PITX2, and PVRL1. The molecular pathways, cellular functions, tissue-specific expression and disease association were investigated using publicly accessible databases (EntrezGene, UniProt, OMIM). The Gene Ontology terms of the biological processes mediated by the candidate genes were used to cluster them using the GOTermMapper (Lewis-Sigler Institute, Princeton University), speculating on six super-clusters: (a) anatomical development, (b) cell division, growth and motility, (c) cell metabolism and catabolism, (d) cell transport, (e) cell structure organization and (f) organ/system-specific processes. This review aims to increase the knowledge on the mechanisms underlying the co-occurrence of tooth agenesis and orofacial clefts, to pave the way for improving targeted (prenatal) molecular diagnosis and finally to reflect on therapeutic or ultimately preventive strategies for these disabling conditions in the future.
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Phan
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.|Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: F
authors.initials: F
authors.lastname: Conte
authors.affiliation: Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: K D
authors.initials: KD
authors.lastname: Khandelwal
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: C W
authors.initials: CW
authors.lastname: Ockeloen
authors.affiliation: Department of Orthodontics, Dentofacial Orthopedics and Pedodontics, Center for Dental and Craniofacial Sciences, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bartzela
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: van Bokhoven
authors.affiliation: Department of Biomedical and Specialty Surgical Sciences, Medical Genetic Unit, University of Ferrara, Ferrara, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Rubini
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands.|Department of Molecular Developmental Biology, Faculty of Science, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences, Nijmegen, The Netherlands. Carine.Carels@kuleuven.be.|Department of Oral Health Sciences, Faculty of Medicine, KU Leuven and University Hospitals KU Leuven, Kapucijnenvoer, 7, 3000, Leuven, Belgium. Carine.Carels@kuleuven.be.
authors.forename: C E L
authors.identifier: 0000-0002-8974-9223
authors.initials: CE
authors.lastname: Carels
mesh_terms: D000848:Anodontia / Q000235:genetics* / Q000503:physiopathology; D001921:Brain / Q000002:abnormalities* / Q000503:physiopathology; D002971:Cleft Lip / Q000235:genetics* / Q000503:physiopathology; D002972:Cleft Palate / Q000235:genetics* / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000235:genetics; D063990:Gene Ontology; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D009928:Organ Specificity; D010641:Phenotype; D014176:Protein Biosynthesis / Q000235:genetics