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.
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Acknowledgements
All the affected individuals, their parents, families, and control individuals from Bonn, Nijmegen, and Leuven who participated in this study. Members of the Nijmegen Cleft Lip and Palate Team: Dr R. Admiraal, Dr W. Borstlap, Dr T. Wagner, Dr M. Nienhuis, Mrs V. Engels, Drs M. Kuijpers, Mrs J. Vanderstappen, Mrs E. Kerkhofs, Prof AM Kuijpers-Jagtman, Mrs M. Kloen, Mrs J. Buchner, and Mrs M. van der Looy and Drs M. Thonissen for their help in the recruitment of the affected individuals; Margrieta Alblas for preparing the DNAs for MIPs. Members of the Cleft Lip and Palate Team of the University Hospitals KU Leuven: Prof Dr V. Vander Poorten, Prof Dr A. Verdonck, Dr T. Dormaar, Drs C. Vergalle, Dr J. Roosenboom for their help in recruiting the affected individuals; Mr B. Vankeirsbilck for preparing the DNAs, and Dr. L. Veken and Dr R. Pfundt for conducting microarray analyses. The research was funded by the DFG (DO 545/8–1, LU 1944–2/1 to KUL)) and the Cluster of Excellence Frankfurt (Macromolecular Complexes).
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Khandelwal, K.D., van den Boogaard, MJ.H., Mehrem, S.L. et al. Deletions and loss-of-function variants in TP63 associated with orofacial clefting. Eur J Hum Genet 27, 1101–1112 (2019). https://doi.org/10.1038/s41431-019-0370-0
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DOI: https://doi.org/10.1038/s41431-019-0370-0
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