TY - JOUR
T1 - Deletions and loss-of-function variants in TP63 associated with orofacial clefting
AU - Khandelwal, Kriti D.
AU - van den Boogaard, Marie José H.
AU - Mehrem, Sarah L.
AU - Gebel, Jakob
AU - Fagerberg, Christina
AU - van Beusekom, Ellen
AU - van Binsbergen, Ellen
AU - Topaloglu, Ozan
AU - Steehouwer, Marloes
AU - Gilissen, Christian
AU - Ishorst, Nina
AU - van Rooij, Iris A.L.M.
AU - Roeleveld, Nel
AU - Christensen, Kaare
AU - Schoenaers, Joseph
AU - Bergé, Stefaan
AU - Murray, Jeffrey C.
AU - Hens, Greet
AU - Devriendt, Koen
AU - Ludwig, Kerstin U.
AU - Mangold, Elisabeth
AU - Hoischen, Alexander
AU - Zhou, Huiqing
AU - Dötsch, Volker
AU - Carels, Carine E.L.
AU - van Bokhoven, Hans
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85062695892&partnerID=8YFLogxK
U2 - 10.1038/s41431-019-0370-0
DO - 10.1038/s41431-019-0370-0
M3 - Article
C2 - 30850703
AN - SCOPUS:85062695892
SN - 1018-4813
VL - 27
SP - 1101
EP - 1112
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 7
ER -