Non‐syndromic cleft lip with or without palate susceptible loci is associated with tooth agenesis

Abstract

Objective Non‐syndromic tooth agenesis (NSTA) may share common genetic factors with non‐syndromic cleft lip with or without cleft palate (NSCL/P). Single‐nucleotide polymorphisms (SNPs) were associated with individual's susceptibility to these anomalies. We selected five NSCL/P‐associated SNPs from our previous genome‐wide association study (GWAS) to test for the associations with NSTA. Materials and methods A total of 677 NSTA cases and 1,144 healthy controls were recruited in this case–control study. Five genome‐wide NSCL/P‐associated SNPs (rs2235371, rs7078160, rs8049367, rs4791774, and rs13041247) were genotyped by TaqMan platform and evaluated for the associations with NSTA using plink software. Results No significant associations between these SNPs and risk of NSTA were observed in the overall analysis and subgroup analysis with the number of missing teeth. However, in the subgroup analysis by tooth position, rs8049367 was nominally associated with mandibular premolar agenesis (Dominant model: ORdom = 0.66, 95% CIdom = 0.47–0.93, pdom = 0.016; Heterozygote model: ORhet = 0.60, 95% CIhet = 0.41–0.88, Phet = 0.008). Rs4791774 showed a nominal association with congenitally missing maxillary canine (Dominant model: ORdom = 0.53, 95% CIdom = 0.28–0.98, pdom = 0.041; Heterozygote model: ORhet = 0.50, 95% CIhet = 0.26–0.97, Phet = 0.041) and premolar (Additive model: OR = 0.59, 95% CI = 0.36–0.96, p = 0.035). Conclusion This study showed that NSCL/P susceptible loci rs8049367 and rs4791774 were probably associated with the risk of NSTA.

Genetic models and approaches to study orofacial clefts

“…Collectively, GWAS approaches have identified over 50 loci associated with an OFC phenotype, making OFCs at least moderately more polygenic than other structural birth defects where GWAS has been less successful (Lupo et al, 2019). This makes OFCs amenable to secondary analyses, such as LD-score regression, risk score analyses, or Mendelian randomization, to identify genetic overlap with related phenotypes, which may include subclinical phenotypes (Chernus et al, 2018), normal facial variation (Howe et al, 2018;Indencleef et al, 2021), tooth agenesis (Fan et al, 2019;Jonsson et al, 2018), among others traits (Dardani et al, 2020;Howe et al, 2020).…”

Genetic Variants in miRNAs Are Associated With Risk of Non-syndromic Tooth Agenesis

“…DNA extraction was conducted according to the protocol of the TIANamp Genomic DNA Kit (TIANGEN, Beijing) (Fan et al, 2018). DNA samples were stored at −80 • C for further manipulation after purity and concentration were measured.…”

Tooth Agenesis Patterns in Orofacial Clefting Using Tooth Agenesis Code: A Meta-Analysis

“…It can be a challenge to delineate the root cause of TA when a cleft is present. TA may share a common genetic etiology with OFC, as indicated by studies reporting more than 26 genes, including but not limited to: MSX1, PAX9, IRF6, TP63, BMP2, BMP4, WNT10A, WNT3, and AXIN2, associated with the co-occurrence of OFC [ 9 , 10 ]. Alternatively, TA may be the physical consequence of the cleft defect itself due to deficiencies in mesenchymal tissue or blood supply [ 11 ] or may be caused by surgical repair [ 12 ].…”