INTRODUCTION: Variants in SMAD4 or BMPR1A cause juvenile polyposis syndrome, a rare autosomal dominant condition characterized by multiple gastrointestinal hamartomatous polyps. A phenotype of attenuated adenomatous polyposis without hamartomatous polyps is rare. METHODS: We describe a retrospective cohort of individuals with SMAD4 or BMPR1A heterozygous germline variants, having ≥10 cumulative colorectal adenomas and/or colorectal cancer without hamartomatous polyps. All individuals had multigene panel and duplication/deletion analysis to exclude other genetic syndromes. RESULTS: The study cohort included 8 individuals. The pathogenic potential of the variants was analyzed. Variants detected included 4 missense variants, 1 nonsense variant, 1 splice site variant, and 2 genomic deletions. Features of pathogenicity were present in most variants, and cosegregation of the variant with polyposis or colorectal cancer was obtained in 7 of the 8 families. Three of 8 individuals had colorectal cancer (age less than 50 years) in addition to the polyposis phenotype. Two individuals had extraintestinal neoplasms (pancreas and ampulla of Vater). DISCUSSION: The clinical phenotype of SMAD4 and BMPR1A variants may infrequently extend beyond the classical juvenile polyposis syndrome phenotype. Applying multigene panel analysis of hereditary cancer-related genes in individuals with unexplained polyposis can provide syndrome-based clinical surveillance for carriers and their family members.

Hamartomatous polyposis syndromes (HPS) are rare cancer-predisposing disorders including Juvenile polyposis (JPS), Peutz–Jeghers (PJS) and PTEN hamartomatous syndromes (PHS). Penetrant mutations in corresponding genes (SMAD4, BMPR1A, STK11, PTEN and AKT1), are usually diagnosed via a next-generation-sequencing gene panel (NGS-GP) for tailored surveillance and preimplantation testing for monogenic disorders (PGT-M). Five probands with HPS phenotype, with no genetic diagnosis per genetic workup, underwent whole-genome sequencing (WGS) that identified structural genetic alterations: two novel inversions in BMPRA1 and STK11, two BMPR1A-deletions, known as founders among Bukharan Jews, and BMPR1A microdeletion. BMPR1A inversion was validated by “junction fragment” amplification and direct testing. PGT-M was performed via multiplex-PCR and enabled successful birth of a non-carrier baby. WGS may be considered for HPS patients with no NGS-GP findings to exclude structural alterations.