Clinical and functional characterisation of the SMAD4 germline variant c.1035C > A in a family with juvenile polyposis syndrome by whole-exome sequencing

Juvenile polyposis syndrome (JPS) is a rare autosomal dominant inherited disease characterised by multiple juvenile polyps. Genes with JPS-associated mutations and their correlation with the phenotype are currently unknown. Gastrointestinal endoscopy results of a 31-year-old female patient showed multiple polyps in the digestive tract, and the presence of juvenile polyps was confirmed by pathological examination. During follow-up, the patient underwent total gastrectomy and polypectomy several times. Five members of this family were diagnosed with JPS, of which two died and three survived. Full exon gene sequencing of eight members of this family revealed a SMAD4 (NM-005359.3) c.1035C > A (p.Cys345*) mutation. This mutation leads to premature codon termination, causing protein truncation. SMAD4 is a pathogenic gene associated with JPS. This is the first report of an association between the c.1035C > A mutation and JPS pathogenesis. Detection of JPS-related mutations in family members with a genetic predisposition for JPS is very important for genetic counselling, surgical intervention, long-term monitoring and follow-up, and drug treatment.