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Skeletal Class III malocclusion with maxillary deficiency is a severe maxillofacial disease with unclear pathogenic mechanisms. We recruited a Han Chinese family who was clinically diagnosed with skeletal Class III malocclusion and maxillary deficiency. Using whole exome sequencing, a missense variant in ADAMTS2 (NM_014244: c.3506G>T: p.G1169V) was identified and predicted as deleterious by in silico tools. We also found ADAMTS2 variants associated with deficient maxillary development in a cohort. ADAMTS2 expression in HEK293 cells showed significant decrease due to the variant, which was also consistent in dental pulp stem cells from the proband and a healthy control. In the adamts2-knockdown zebrafish model, the length and width of the ethmoid plate, as well as the length of the palatoquadrate became significantly shorter than the control group (p < 0.001), while there was no significant difference in the length and width of the mandible. The expression of Sox3, which was required in early embryonic craniofacial development, was significantly downregulated in the adamts2-knockdown zebrafish embryos. Bioinformatic and cellular studies showed that the decreased expression of ADAMTS2 may inhibit downstream ErbB signaling pathway transduction and restrain subsequent osteogenesis in human adult mesenchymal stromal cells. Collectively, these data showed that ADAMTS2 (c.3506G>T: p.G1169V) may confer susceptibility to risk of skeletal Class III malocclusion with maxillary deficiency. [ABSTRACT FROM AUTHOR]

Although several genome‐wide association studies (GWAS) of non‐syndromic cleft lip with or without cleft palate (NSCL/P) have been reported, more novel association signals are remained to be exploited. Here, we performed an in‐depth analysis of our previously published Chinese GWAS cohort study with replication in an extra dbGaP case‐parent trios and another in‐house Nanjing cohort, and finally identified five novel significant association signals (rs11119445: 3' of SERTAD4, P = 6.44 × 10−14; rs227227 and rs12561877: intron of SYT14, P = 5.02 × 10−13 and 2.80 × 10−11, respectively; rs643118: intron of TRAF3IP3, P = 4.45 × 10−6; rs2095293: intron of NR6A1, P = 2.98 × 10−5). The mean (standard deviation) of the weighted genetic risk score (wGRS) from these SNPs was 1.83 (0.65) for NSCL/P cases and 1.58 (0.68) for controls, respectively (P = 2.67 × 10−16). Rs643118 was identified as a shared susceptible factor of NSCL/P among Asians and Europeans, while rs227227 may contribute to the risk of NSCL/P as well as NSCPO. In addition, sertad4 knockdown zebrafish models resulted in down‐regulation of sox2 and caused oedema around the heart and mandibular deficiency, compared with control embryos. Taken together, this study has improved our understanding of the genetic susceptibility to NSCL/P and provided further clues to its aetiology in the Chinese population. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify a pathogenic mutation located in TP63 in a nuclear Han Chinese family. Whole-exome sequencing and Sanger sequencing were performed to identify candidate variants. The AlphaFold and PyMOL predicted the three-dimensional structure of the protein. Single-cell RNA-sequencing data and spatiotemporal transcriptomic atlas were used to generate the dissection of candidate gene expression at single-cell resolution. Significant genes (Pearson's coefficient ≥ 0.8 and P < 0.05) were identified for Gene Ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathways analysis. A heterozygous missense variant at TP63 exon 8 (c.1010 G>A:p.Arg337Gln) was identified in the proband. This variant was predicted deleterious and likely to impair the local stability of the protein. In addition, single-cell RNA-sequencing indicated that TP63 was highly expressed in skin tissues. Furthermore, spatial transcriptome data of mice embryos showed TP63 was mainly enriched in the mucosal epithelium, thymus, epidermis, mesenchyme, and surface ectoderm. GO and KEGG pathway annotation analysis revealed that TP63 played a positive role in the process of ectoderm via the TGF-beta signaling pathway. The missense variant of TP63 (c.1010 G>A:p.Arg337Gln) was associated with ectodermal dysplasia. • A heterozygous missense variant at TP63 was associated with ectodermal dysplasia. • Individuals with TP63 variants showed variable traits with ectodermal dysplasia. • TP63 impacted ectodermal development via the TGF-beta signaling pathway. [ABSTRACT FROM AUTHOR]