A New SMAD4 Splice Site Variant in a Three-Generation Italian Family with Juvenile Polyposis Syndrome

Abstract

Juvenile polyposis syndrome (JPS) is an autosomal dominant disorder characterized by hyperplastic polyps in the upper and lower gastrointestinal (GI) tract with a high risk of developing GI cancers. We have described a three-generation Italian family with all the spectrum of SMAD4 phenotype. A multigene panel test was performed on the genomic DNA of the proband by next-generation sequencing, including genes related to hereditary GI tumor syndromes. Molecular analysis revealed the presence of the c.1140-2A>G substitution in the SMAD4 gene, a novel splice variant that has never been described before. Our family is remarkable in that it illustrates the variable expressivity of the SMAD4 phenotype within the same family. The possibility of phenotype variability should also be considered within family members carrying the same mutation. In JPS, a timely genetic diagnosis allows clinicians to better manage patients and to provide early surveillance and intervention for their asymptomatic mutated relatives in the early decades of life.

Studying the Effect of Host Genetic Background of Juvenile Polyposis Development using Collaborative Cross and Smad4 Knock-out Mouse Models

“…Most of this increased risk is attributed to colon cancer, but stomach, upper gastrointestinal tract, and pancreas cancers have also been reported [3,[9][10][11][12]. Even among patients of the same age, the polyp shapes and sizes vary, and it is possible to notice this even among members of the same family who have JPS [13].…”

Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models

“…Most of this increased risk is attributed to colon cancer, but the stomach, upper gastrointestinal tract, and pancreatic cancers have also been reported [ 3 , 9 , 10 , 11 , 12 ]. Even among patients of the same age, polyp shapes and sizes vary; it is possible to notice this even among members of the same family who have JPS [ 13 ].…”