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

Autor: Anikó Bozsik, Henriett Butz, Vince Kornél Grolmusz, Csaba Polgár, Attila Patócs, János Papp
Rok vydání: 2023
Předmět:
Zdroj: European Journal of Human Genetics.
ISSN: 1476-5438
1018-4813
Popis: Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome that occurs as a result of germline mutations in the APC gene. Despite a clear clinical diagnosis of FAP, a certain proportion of the APC variants are not readily detectable through conventional genotyping routines. We accomplished genome sequencing in duo of the disease-affected proband and non-affected sibling followed by in silico predictions and a series of RNA-based assays clarifying variant functionality. By prioritizing variants obtained by genome sequencing, we discovered the novel deep intronic alteration APC:c.531 + 1482 A > G that was demonstrated to cause out-of-frame exonization of 56 base pairs from intron 5 of the gene. Further cDNA assays confirmed, that the aberrant splicing event was complete and its splice product was subject to nonsense-mediated decay. Co-segregation was observed between the variant carrier status and the disease phenotype. Cumulative evidence confirmed that APC:c.531 + 1482 A > G is a pathogenic variant causative of the disease.
Databáze: OpenAIRE
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