Ectodermal dysplasia

Gene: LRP6

Green List (high evidence)

The rating of this gene has been updated to green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.

Created: 6 Dec 2024, 12:48 p.m. | Last Modified: 6 Dec 2024, 12:48 p.m.

Panel Version: 3.35

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Green List (high evidence)

Massink et al. (2015) report the first association between LRP6 and oligodontia. LRP6 is a major component of the Wnt receptor complex in the canonical Wnt pathway. Other genes involved in this pathway, such as WNT10A, have been shown to be associated with oligodontia as well.
4 unrelated individuals with nonsyndromic oligodontia (12-20 missing teeth each) are reported: 3 carry heterozygous truncating variants in the LRP6 gene, and 1 carries a missense variant (p.Ala19Val) of a conserved residue located at the cleavage site of the protein's signal peptide. Functional studies showed that the missense variant results in altered glycosylation and improper subcellular localisation of the protein, resulting in abrogated activation of the Wnt pathway. Segregation studies confirmed presence of the variants in 6 additional affected family members across the 3 families with truncating variants. Incomplete penetrance was observed in the family of the individual with the missense variant, where the mother was found to be a carrier and is unaffected.
Lastly, an affected father and 2 daughters showed minor anatomical variation of the ear and underdevelopment of the thumb. No other anomalies described in the cohort.
Ockeloen et al. (2016) report 2 additional probands with oligodontia, one of which also had orofacial cleft, and perform a study among 67 patients with tooth agenesis, 1,073 patients with orofacial clefts, and 706 controls. They found significant enrichment of LRP6 rare variants in patients with tooth agenesis, but not in patients with nonsyndromic orofacial clefts. Five variants were identified in patients with tooth agenesis and shown to segregate in the 4 families (1 variant was de novo). Immunochemistry studies on embryonic mice showed that the gene is expressed in areas of bone formation, including the tooth follicle, suggesting a role in early tooth development.
Therefore, this gene should be promoted GREEN in this panel.

Created: 16 Aug 2023, 2:39 p.m. | Last Modified: 16 Aug 2023, 2:39 p.m.

Panel Version: 3.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Tooth agenesis, selective, 7, OMIM:616724

Publications

• 26387593
• 26963285