WNT10B – Tooth Agenesis

Isolated tooth agenesis, ranging from hypodontia to oligodontia, is a frequent congenital dental anomaly. Heterozygous variants in several WNT pathway genes underlie autosomal dominant forms of tooth agenesis. WNT10B, a paralog of WNT10A, has emerged as a contributor to non‐syndromic dental agenesis and related anomalies in multiple cohorts.

In a Thai cohort of 256 unrelated families, four heterozygous missense variants in WNT10B were detected in seven families afflicted with dental anomalies ([PMID:29364501]). The recurrent variant c.475G>C (p.Ala159Pro) was identified in four families and c.1052G>A (p.Arg351His) in one family, with no pathogenic alleles in other known hypodontia genes. Affected individuals exhibited oligodontia, microdontia (HP:0000691), short dental roots (HP:0006336), pulp stones (HP:0003771), and taurodontia (HP:0000679).

Whole‐exome sequencing in Chinese families revealed a heterozygous missense variant c.632G>A (p.Arg211Gln) segregating with oligodontia across all affected members ([PMID:27321946]). Subsequent screening of 145 unrelated individuals with non‐syndromic oligodontia identified three additional WNT10B variants: c.569C>G (p.Pro190Arg), c.343C>T (p.Arg115Ter), and c.786G>A (p.Trp262Ter).

Segregation analysis demonstrated complete co‐segregation of c.632G>A with tooth agenesis in a multiplex family (n=4 affected relatives) ([PMID:27321946]). Independent identification of WNT10B variants in multiple unrelated families supports an autosomal dominant inheritance pattern with variable expressivity.

Functional studies in HEPG2 cells using TOPFlash luciferase assays showed that WNT10B mutants fail to activate canonical Wnt signaling, consistent with a loss‐of‐function mechanism ([PMID:27321946]). In SHED cells, the rs833843 variant did not significantly alter expression of downstream TA genes, suggesting context‐specific effects ([PMID:33369218]).

Collectively, heterozygous WNT10B variants have been reported in at least 11 unrelated probands with non‐syndromic tooth agenesis, supported by segregation in a multiplex kindred and concordant in vitro functional assays. Further large‐scale segregation studies and in vivo models will strengthen the association. Key take‐home: WNT10B should be included in gene panels for genetic diagnosis of autosomal dominant tooth agenesis.

References

• Clinical genetics • 2018 • WNT10B mutations associated with isolated dental anomalies. PMID:29364501
• American journal of human genetics • 2016 • Mutations in WNT10B Are Identified in Individuals with Oligodontia. PMID:27321946
• Orthodontics & craniofacial research • 2021 • Functional characterization of ATF1, GREM2 AND WNT10B variants associated with tooth agenesis. PMID:33369218

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