Deletions and loss-of-function variants in TP63 associated with orofacial clefting

Kriti D Khandelwal, Marie-José H van den Boogaard, Sarah L Mehrem, Jakob Gebel, Christina Fagerberg, Ellen van Beusekom, Ellen van Binsbergen, Ozan Topaloglu, Marloes Steehouwer, Christian Gilissen, Nina Ishorst, Iris A L M van Rooij, Nel Roeleveld, Kaare Christensen, Joseph Schoenaers, Stefaan Bergé, Jeffrey C Murray, Greet Hens, Koen Devriendt, Kerstin U LudwigElisabeth Mangold, Alexander Hoischen, Huiqing Zhou, Volker Dötsch, Carine E L Carels, Hans van Bokhoven*

*Kontaktforfatter for dette arbejde

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review


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.

TidsskriftEuropean Journal of Human Genetics
Udgave nummer7
Sider (fra-til)1101-1112
StatusUdgivet - jul. 2019



Khandelwal, K. D., van den Boogaard, M-J. H., Mehrem, S. L., Gebel, J., Fagerberg, C., van Beusekom, E., van Binsbergen, E., Topaloglu, O., Steehouwer, M., Gilissen, C., Ishorst, N., van Rooij, I. A. L. M., Roeleveld, N., Christensen, K., Schoenaers, J., Bergé, S., Murray, J. C., Hens, G., Devriendt, K., ... van Bokhoven, H. (2019). Deletions and loss-of-function variants in TP63 associated with orofacial clefting. European Journal of Human Genetics, 27(7), 1101-1112.