Case Report: BMPR1A and BARD1 variants: first case identified in a Colombian family with juvenile polyposis syndrome.

Juvenile polyposis syndrome (JPS) is a rare autosomal-dominant disorder characterized by numerous juvenile hamartomatous polyps in the gastrointestinal tract (GIT), increasing cancer risk. Pathogenic and likely pathogenic (P/LP) variants in the SMAD4 or BMPR1A genes are associated with JPS. Here, we present a case of JPS with variants in BMPR1A and BARD1. This case involves a 62-year-old Colombian woman with multiple colorectal polyps. Family history included gastric cancer in the mother and the paternal grandmother, and colorectal polyps in two sisters and one daughter. Germline testing of the proband identified a novel heterozygous frameshift variant in exon 11 of BMPR1A (NM_004329.3:c.1259dup) and a heterozygous frameshift variant in exon 11 of BARD1 (NM_000465.4:c.2229dup), both predicted to introduce premature stop codons. The variants were validated by Sanger sequencing and evaluated by KASP genotyping in available relatives. In the JPS family, the BMPR1A variant was detected in the affected daughter and was absent in the tested unaffected relatives, supporting a presumed de novo origin, although parental testing was not available. In an independent case of cecal adenocarcinoma identified among 18 unrelated index cases, parental testing confirmed the de novo origin of the BMPR1A variant. To our knowledge, these variants have not yet been described in Colombia. Germline genetic testing revealed for the first time the presence of a possible novel de novo pathogenic variant in BMPR1A in a family with JPS and a case with an adenocarcinoma and family history of cancer, which may partially explain the etiology of the syndrome and facilitate cancer risk management for the other family members. In addition, the likely pathogenic variant in BARD1 identified in our proband may be either incidental or causal. This latter gene is associated with an increased risk of breast cancer; however, additional evidence is required to support the role of this gene in the risk of JPS or GIT cancer.