LRP6 β-Propeller Destabilization: Novel Variant, Phenotype and Diagnostic Implications in Tooth Agenesis

Area of Science:

• Genetics
• Developmental Biology
• Oral Health

Background:

• Oligodontia, the congenital absence of multiple permanent teeth, is often associated with Low-density lipoprotein receptor-related protein 6 (LRP6) variants.
• Understanding genotype-phenotype correlations and representation of diverse ethnic groups in LRP6 research is limited.

Purpose of the Study:

• To molecularly and clinically characterize LRP6 variants in Thai individuals with tooth agenesis.
• To perform a scoping review of published LRP6 variant cases.
• To refine the understanding of LRP6 genotype-phenotype correlations in tooth agenesis.

Main Methods:

• Case series analysis of Thai families using exome sequencing and 3D protein modeling.
• Functional validation via computational structural prediction.
• PRISMA-ScR-guided scoping review of LRP6 variant studies (2005-2025).

Main Results:

• A novel heterozygous de novo missense variant, p.Asp411Tyr, was identified, destabilizing the LRP6 β-propeller domain.
• Thai probands expanded the known phenotype and genotype spectrum of LRP6-associated tooth agenesis, including rare ectodermal features.
• A review of 20 studies confirmed variant clustering in LRP6 β-propeller domains, predominantly autosomal dominant inheritance with variable penetrance.

Conclusions:

• LRP6 is a significant mutational hotspot in tooth development.
• LRP6-associated tooth agenesis exhibits variable phenotypic expressivity and penetrance.
• This study enhances the understanding of LRP6's role in tooth agenesis across diverse populations.