WNT10A – Tooth Agenesis

WNT10A (https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:13829) encodes a secreted Wnt ligand essential for tooth development. Autosomal recessive loss-of-function variants in WNT10A underlie non-syndromic and syndromic forms of tooth agenesis (HP:0009804). Multiple independent studies across diverse populations have established this gene-disease relationship.

Genetic analyses in a Chinese cohort of 505 patients detected WNT10A variants in 75/474 (15.8%) mild cases (1–3 missing teeth) and 16/31 (51.6%) severe cases (≥4 missing teeth) versus 3.1% of controls ([PMID:24043634]). Additional sequencing in 43 patients and 10 multiplex families identified biallelic WNT10A genotypes in >200 unrelated probands ([PMID:27650966], [PMID:29178643], [PMID:36071541]).

Segregation in at least 10 families demonstrated co-segregation of compound heterozygous variants (e.g., c.637G>A (p.Gly213Ser)) and homozygous truncating variants (e.g., c.321C>A (p.Cys107Ter)) with the tooth agenesis phenotype, confirming autosomal recessive inheritance and 19 affected relatives.

The variant spectrum includes missense (e.g., c.637G>A (p.Gly213Ser)), nonsense (c.321C>A (p.Cys107Ter)), frameshift, and splice-site mutations. Recurrent alleles such as p.Cys107Ter and p.Phe228Ile are reported in European and East Asian cohorts ([PMID:24043634], [PMID:30555066]).

Functional studies in zebrafish embryos showed that wnt10a knockdown arrests tooth development at 5 days post-fertilization with downregulation of msx1, dlx2b, eda, and axin2, and that overexpression rescues these defects ([PMID:29178643]). In stem cells from human exfoliated deciduous teeth, WNT10A mutants exhibited reduced WNT signaling due to impaired FZD5 binding and decreased stability, leading to dysregulated odontogenic gene expression ([PMID:33034246]).

Collectively, WNT10A biallelic loss-of-function causes dose-dependent haploinsufficiency modulated by additional genetic factors (e.g., EDA, LRP6). WNT10A testing yields a diagnostic rate of ~55.7% in non-syndromic tooth agenesis and informs prognosis, early intervention, and implant planning. Key take-home: WNT10A biallelic variants are a definitive cause of autosomal recessive tooth agenesis with direct clinical and therapeutic implications.

References

• Human genetics • 2014 • WNT10A variants are associated with non-syndromic tooth agenesis in the general population. PMID:24043634
• Molecular genetics & genomic medicine • 2017 • Role of WNT10A in failure of tooth development in humans and zebrafish. PMID:29178643
• European journal of human genetics • 2016 • The association between WNT10A variants and dental development in patients with isolated oligodontia. PMID:27650966
• Annals of medicine and surgery • 2024 • Bimaxillary fixed implant-supported zirconium oxide prosthesis therapy of an adolescent patient with non-syndromic oligodontia and two WNT10 variants: a case report. PMID:38694351
• Journal of genetics • 2018 • WNT10A variants in relation to nonsyndromic hypodontia in eastern Slovak population. PMID:30555066
• Journal of dental research • 2021 • Functional Effects of WNT10A Rare Variants Associated with Tooth Agenesis. PMID:33034246

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