Solving Missing Heritability in Patients With Familial Adenomatous Polyposis With DNA-RNA Paired Testing

Area of Science:

• Genetics
• Molecular Biology
• Oncology

Background:

• Germline pathogenic variants (PVs) in the APC gene are linked to familial adenomatous polyposis (FAP) and attenuated FAP (AFAP), increasing colorectal cancer risk.
• A significant percentage of FAP/AFAP patients lack identified PVs after DNA-only multigene panel testing (MGPT).

Purpose of the Study:

• To evaluate the utility of concurrent DNA and RNA sequencing (MGPT) in detecting germline PVs in individuals with FAP/AFAP phenotypes.
• To demonstrate improved diagnostic yield compared to DNA-only testing.

Main Methods:

• Retrospective analysis of paired DNA-RNA MGPT data from 2021-2022.
• Inclusion criteria: novel APC PVs in intronic regions, personal history of polyposis, and family history.

Main Results:

• Three novel APC variants were identified in six families, causing aberrant splicing due to cryptic splice sites.
• These variants led to RNA transcripts subject to nonsense-mediated decay.
• Some carriers had previously tested negative with DNA-only genetic testing.

Conclusions:

• Paired DNA-RNA MGPT effectively identifies previously undetected germline PVs in APC, addressing missing heritability in FAP families.
• This enhanced diagnostic capability has significant implications for patient management, family planning, and treatment decisions.