Novel IRF6 Mutations Detected in Orofacial Cleft Patients by Targeted Massively Parallel Sequencing.
Common variants in interferon regulatory factor 6 ( IRF6) have been associated with nonsyndromic cleft lip with or without cleft palate (NSCL/P) as well as with tooth agenesis (TA). These variants contribute a small risk towards the 2 congenital conditions and explain only a small percentage of heritability. On the other hand, many IRF6 mutations are known to be a monogenic cause of disease for syndromic orofacial clefting (OFC). We hypothesize that IRF6 mutations in some rare instances could also cause nonsyndromic OFC. To find novel rare variants in IRF6 responsible for nonsyndromic OFC and TA, we performed targeted multiplex sequencing using molecular inversion probes (MIPs) in 1,072 OFC patients, 67 TA patients, and 706 controls. We identified 3 potentially pathogenic de novo mutations in OFC patients. In addition, 3 rare missense variants were identified, for which pathogenicity could not unequivocally be shown, as all variants were either inherited from an unaffected parent or the parental DNA was not available. Retrospective investigation of the patients with these variants revealed the presence of lip pits in one of the patients with a de novo mutation suggesting a Van der Woude syndrome (VWS) phenotype, whereas, in other patients, no lip pits were identified.
1 Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
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Khandelwal
2 Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|3 Institute of Human Genetics, Biomedical Center, University of Bonn, Bonn, Germany.
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Ishorst
4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|5 Department of Molecular Developmental Biology, Radboud Institute for Molecular Life Sciences, Radboud University, Nijmegen, The Netherlands.
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Zhou
2 Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany.|3 Institute of Human Genetics, Biomedical Center, University of Bonn, Bonn, Germany.
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Ludwig
6 Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands.
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Venselaar
4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|7 Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
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Gilissen
1 Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
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Thonissen
8 Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
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van Rooij
1 Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
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Dreesen
4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
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Steehouwer
4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
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van de Vorst
1 Department of Orthodontics and Craniofacial Biology, Radboud University Medical Center, Nijmegen, The Netherlands.
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Bloemen
4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
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van Beusekom
9 Department of Neurosciences, Experimental Otorhinolaryngology, AGORA-Research Group, KU Leuven, Leuven, Belgium.
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Roosenboom
10 Department of Oral and Maxillofacial Surgery, Radboud University Medical Center, Nijmegen, The Netherlands; Cleft Palate Craniofacial Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
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Borstlap
11 Hearing & Genes Division, Department of Otorhinolaryngology, Radboud University Medical Center, Nijmegen. GA, The Netherlands; Cleft Palate Craniofacial Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
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Admiraal
12 Department of Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium; Leuven Cleft Lip and Palate Team, KU Leuven, Leuven, Belgium.
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Dormaar
12 Department of Oral and Maxillofacial Surgery, University Hospitals Leuven, Leuven, Belgium; Leuven Cleft Lip and Palate Team, KU Leuven, Leuven, Belgium.
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Schoenaers
13 Otorhinolaryngology-Head and Neck Surgery, University Hospitals Leuven, Belgium; Leuven Cleft Lip and Palate Team, University Hospitals KU Leuven, Leuven, Belgium.
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Vander Poorten
13 Otorhinolaryngology-Head and Neck Surgery, University Hospitals Leuven, Belgium; Leuven Cleft Lip and Palate Team, University Hospitals KU Leuven, Leuven, Belgium.
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Hens
14 Department of Orthodontics, University Hospitals Leuven, Belgium; Leuven Cleft Lip and Palate Team, AGORA-Research Group, University Hospitals KU Leuven, Leuven, Belgium.
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Verdonck
10 Department of Oral and Maxillofacial Surgery, Radboud University Medical Center, Nijmegen, The Netherlands; Cleft Palate Craniofacial Centre, Radboud University Medical Center, Nijmegen, The Netherlands.
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Bergé
8 Radboud Institute for Health Sciences, Department for Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.
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Roeleveldt
6 Centre for Molecular and Biomolecular Informatics, Radboud University Medical Center, Nijmegen, The Netherlands.
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Vriend
15 Department of Clinical Genetics, Center for Human Genetics, University Hospitals KU Leuven, Leuven, Belgium.
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Devriendt
4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
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Brunner
3 Institute of Human Genetics, Biomedical Center, University of Bonn, Bonn, Germany.
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Mangold
4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|7 Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
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Hoischen
4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|7 Department of Cognitive Neurosciences, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
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van Bokhoven
4 Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.|16 Department of Oral Health Sciences, AGORA-Research Group, University Hospitals KU Leuven, Leuven, Belgium.
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Carels
D000015:Abnormalities, Multiple / Q000235:genetics; D002971:Cleft Lip / Q000235:genetics*; D002972:Cleft Palate / Q000235:genetics*; D003560:Cysts / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D008046:Lip / Q000002:abnormalities; D009154:Mutation / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D017422:Sequence Analysis, DNA
C109803:IRF6 protein, human; D050835:Interferon Regulatory Factors
cleft lip; cleft palate; genetics; high-throughput nucleotide sequencing; hypodontia; risk factor(s)