Journal article
Deletions and loss-of-function variants in TP63 associated with orofacial clefting
European journal of human genetics : EJHG, Vol.27(7), pp.1101-1112
07/01/2019
DOI: 10.1038/s41431-019-0370-0
PMCID: PMC6777535
PMID: 30850703
Abstract
We aimed to identify novel deletions and variants of TP63 associated with orofacial clefting (OFC). Copy number variants were assessed in three OFC families using microarray analysis. Subsequently, we analyzed TP63 in a cohort of 1072 individuals affected with OFC and 706 population-based controls using molecular inversion probes (MIPs). We identified partial deletions of TP63 in individuals from three families affected with OFC. In the OFC cohort, we identified several TP63 variants predicting to cause loss-of-function alleles, including a frameshift variant c.569_576del (p.(Ala190Aspfs*5)) and a nonsense variant c.997C>T (p.(Gln333*)) that introduces a premature stop codon in the DNA-binding domain. In addition, we identified the first missense variants in the oligomerization domain c.1213G>A (p.(Val405Met)), which occurred in individuals with OFC. This variant was shown to abrogate oligomerization of mutant p63 protein into oligomeric complexes, and therefore likely represents a loss-of-function allele rather than a dominant-negative. All of these variants were inherited from an unaffected parent, suggesting reduced penetrance of such loss-of-function alleles. Our data indicate that loss-of-function alleles in TP63 can also give rise to OFC as the main phenotype. We have uncovered the dosage-dependent functions of p63, which were previously rejected.
Details
- Title: Subtitle
- Deletions and loss-of-function variants in TP63 associated with orofacial clefting
- Creators
- Kriti D Khandelwal - Radboud Institute for Molecular Life SciencesMarie-José H van den Boogaard - University Medical Center UtrechtSarah L Mehrem - Life & BrainJakob Gebel - Goethe University FrankfurtChristina Fagerberg - Odense University HospitalEllen van Beusekom - Radboud University Medical CenterEllen van Binsbergen - University Medical Center UtrechtOzan Topaloglu - Radboud Institute for Molecular Life SciencesMarloes Steehouwer - Radboud Institute for Molecular Life SciencesChristian Gilissen - Radboud Institute for Molecular Life SciencesNina Ishorst - University Hospital BonnIris A L M van Rooij - Radboud University Medical CenterNel Roeleveld - Radboud University Medical CenterKaare Christensen - Odense University HospitalJoseph Schoenaers - KU LeuvenStefaan Bergé - Radboud University Medical CenterJeffrey C Murray - University of IowaGreet Hens - KU LeuvenKoen Devriendt - Center for Human GeneticsKerstin U Ludwig - University Hospital BonnElisabeth Mangold - University Hospital BonnAlexander Hoischen - Radboud Institute for Molecular Life SciencesHuiqing Zhou - Radboud Institute for Molecular Life SciencesVolker Dötsch - Goethe University FrankfurtCarine E L Carels - Department of Human Genetics, Centre for Human Genetics, KU Leuven and University Hospitals KU Leuven, Leuven, Belgium. carine.carels@uzleuven.beHans van Bokhoven - Radboud University Nijmegen
- Resource Type
- Journal article
- Publication Details
- European journal of human genetics : EJHG, Vol.27(7), pp.1101-1112
- DOI
- 10.1038/s41431-019-0370-0
- PMID
- 30850703
- PMCID
- PMC6777535
- NLM abbreviation
- Eur J Hum Genet
- ISSN
- 1018-4813
- eISSN
- 1476-5438
- Language
- English
- Date published
- 07/01/2019
- Academic Unit
- Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9985034984202771
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