LRP6 β-Propeller Destabilization: Novel Variant, Phenotype and Diagnostic Implications in Tooth Agenesis
- Narin Intarak, Tohid Ghasemnejad, Kausar Sadia Fakhruddin, Ayaana Kamal, Sasiprapa Prommanee, Khadijeh Hoda Jahanian, Nigel H Lovell, Hamid Alinejad-Rokny, Thantrira Porntaveetus
- https://doi.org/10.1016/j.identj.2025.109367
Abstract
Background and Objectives
Oligodontia, the congenital absence of multiple permanent teeth, is frequently linked to LRP6 variants. However, the genotype–phenotype correlations remain unclear and non-European cohorts are underrepresented. The objectives of this study were to: (1) characterize the molecular and clinical features of LRP6 variants identified in unrelated Thai individuals with tooth agenesis; (2) conduct a scoping review of previously published cases; and (3) refine the understanding of LRP6 genotype–phenotype correlations.
Materials and Methods
A detailed case series analysis of Thai families with congenital tooth agenesis (through exome sequencing and 3D protein modelling) was conducted, and functional validation was performed using computational structural prediction. A reviewed published cases of LRP6 variants was performed following a PRISMA-ScR-guided scoping review (2005-2025).
Results
p.Asp411Tyr, a novel heterozygous de novo missense change, destabilised the β-propeller domain. While Thai probands expanded the phenotype and genotype spectrum of LRP6-associated tooth agenesis, a review of 20 studies showed clustering of variants in β-propeller domains (62%), usually autosomal dominant (78%) but with variable penetrance. The phenotypes ranged from isolated oligodontia to syndromic forms. Thai probands displayed rare ectodermal-associated features (preauricular pits, dry skin) expanding the spectrum.
Conclusion
LRP6 is a mutational hotspot in tooth development, with variable phenotypical expressivity and penetrance.