Genome sequencing-based discovery of a novel deep intronic APC pathogenic variant causing exonization

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• Familial adenomatous polyposis (FAP) is an inherited cancer syndrome linked to APC gene mutations.
• Conventional genetic testing sometimes fails to detect all causative APC variants.

Purpose of the Study:

• To identify novel pathogenic APC variants in FAP patients.
• To characterize the functional impact of a newly discovered intronic variant.

Main Methods:

• Whole-genome sequencing of affected and unaffected family members.
• In silico variant prediction and RNA-based functional assays.
• cDNA analysis to confirm splicing defects and co-segregation studies.

Main Results:

• A novel deep intronic variant, APC:c.531+1482A>G, was identified.
• This variant causes exonization of 56 base pairs from intron 5, leading to aberrant splicing.
• The aberrant splice product undergoes nonsense-mediated decay, confirming pathogenicity.

Conclusions:

• APC:c.531+1482A>G is a pathogenic variant causing FAP.
• Advanced genomic and functional analyses are crucial for detecting cryptic genetic alterations in hereditary cancer syndromes.