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

## TL;DR

This study identifies a new LRP6 gene variant linked to tooth agenesis in Thai individuals and expands the known clinical features of this condition.

## Contribution

A novel LRP6 variant (p.Asp411Tyr) is identified, showing destabilization of the β-propeller domain and expanding the phenotypic spectrum in tooth agenesis.

## Key findings

- The p.Asp411Tyr variant destabilizes the β-propeller domain of LRP6.
- Thai probands exhibit rare ectodermal features like preauricular pits and dry skin.
- LRP6 variants cluster in β-propeller domains and show variable penetrance and expressivity.

## Abstract

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.

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).

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.

LRP6 is a mutational hotspot in tooth development, with variable phenotypical expressivity and penetrance.