Insights in germline genetic variation in Hereditary Polyposis Syndromes Patients from Argentina and Chile: identification of 4 novel variants

Abstract

We aimed to identify novel genetic variants in 81 unrelated probands from Argentina and Chile with hereditary polyposis syndromes (Familial Adenomatous Polyposis, FAP, and Hamartomatous). By whole exome sequencing and MLPA, we identified pathogenic variants in 19.8% (16/81) of individuals and included APC (75%, 12/16), MUTYH (18.8%, 3/16) and SMAD4 (6.2%, 1/16) genes. As expected, more than 50% (17/33) of the variants were VUS, being 15 identified in APC, 1 in SMAD4 and 1 in POLE genes. We identified 4 novel potentially pathogenic germline variants in 4.9% (4/81) patients, including APC c.1271dupA (p.E425Gfs*4), c.532T>A (p.F178I), c.4948A>T (p.N1650Y), and SMAD4 c.742C>T (p.Q248*). By analyzing MUTYH gene, we found 2/3 probands carrying compound heterozygous pathogenic SNVs: c.289C>T (p.R97*)/c.1227_1228dupGG (p.E410Gfs*), c.536A>G (p.Y179C)/c.1187G>A (p.G396D). The third case showed a homozygous pathogenic SNV, c.1187G>A (p.G396D). We described a correlation between the identified pathogenic germline variant and the clinical phenotype where 80% of carriers of APC pathogenic variants, having ≥100 colonic adenomatous polyps, developed colorectal cancer (CRC, at mean age=33.5y) and/or has polyposis and CRC family history. Our study enlarges the spectrum of causal variants in other genes than APC and the genotype/phenotype correlation in Argentinean and Chilean patients. Our results may have a direct impact on providing an appropriate genetic counseling and clinical management for individuals and their relatives who carry these variants. The high percentage of identified VUS support the notion that more studies addressing the biological consequence are strongly required, for so improve the translation of genetic research findings into patient care.