A novel AXIN2 germline variant associated with attenuated FAP without signs of oligondontia or ectodermal dysplasia

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome.
• AXIN2 gene mutations have been associated with FAP and ectodermal dysplasia.
• The precise role of AXIN2 in FAP pathogenesis requires further elucidation.

Purpose of the Study:

• To investigate the genetic basis of FAP in families negative for APC and MUTYH mutations.
• To identify novel genetic factors contributing to FAP development.
• To characterize the clinical phenotype associated with AXIN2 alterations.

Main Methods:

• Exclusion of APC and MUTYH mutations in 23 FAP families.
• Whole-exome sequencing and targeted gene analysis of Wnt pathway genes.
• Functional validation of a novel AXIN2 variant through LOH analysis, segregation studies, and protein expression analysis.

Main Results:

• A novel missense variant in the AXIN2 gene was identified in one family with attenuated FAP.
• AXIN2 variant carriers presented with variable polyp burden but no ectodermal dysplasia.
• Functional studies confirmed the pathogenicity of the novel AXIN2 variant.

Conclusions:

• This study expands the phenotypic spectrum of AXIN2 alterations in FAP.
• AXIN2 should be considered for genetic screening in FAP cases negative for APC and MUTYH mutations.
• Further research is warranted to understand the genotype-phenotype correlation of AXIN2 variants in FAP.