Expanding the Genetic Spectrum of Hereditary Polyposis Syndromes: A Multicenter Study from Argentina

Hereditary polyposis syndromes (HPS) predispose to colorectal cancer, yet their genetic landscape in Argentina remains underrepresented. We analyzed 177 probands from 163 unrelated families recruited through three Argentine reference centers. Genetic testing included APC and MUTYH analysis by Sanger sequencing and MLPA, complemented by multigene panels and whole-exome sequencing (WES). Variants were classified following ACMG/AMP guidelines. Germline APC variants were identified in 75/177 probands (42.4%), pathogenic MUTYH variants in 11 (6.2%), and alterations in BMPR1A and SMAD4 in 2 probands each. Within the APC -positive subset, 52 unique variants were detected, including seven novel truncating frameshift mutations and six large genomic rearrangements. Segregation analysis supported pathogenicity in available families. Genotype–phenotype correlations confirmed the enrichment of truncating variants within the mutation cluster region (MCR) in classic FAP, whereas distal variants predominated in attenuated forms. This first large-scale Argentine study characterizes APC - and MUTYH -related polyposis in the region. The identification of novel APC alleles and regionally recurrent MUTYH variants broadens the national reference framework, providing critical evidence to improve genetic diagnosis and clinical management in this specific population.