BMPR1A was first reported in relation to Autosomal Dominant Juvenile Polyposis Syndrome (JPS) in 2001 (PMID 11381269). Juvenile Polyposis Syndrome is characterized by multiple gastrointestinal polyps and a predisposition to gastrointestinal cancer. A very small fraction of JPS patients (around 9%) have cardiovascular defects (PMID: 32398773). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) and inheritance pattern. Therefore, the following disease entities have been lumped into one disease entities, JPS (OMIM # 174900) and hereditary mixed polyposis syndrome-2 (HMPS2, OMIM # 610069). 17 variants (including missense, nonsense, and frameshift variants) reported in 17 probands in 5 publications (PMIDs: 15235019, 11381269, 11536076, 12136244, 17325551, 26171675) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. Multiple gastrointestinal polyps are universally reported in JPS patients with BMPR1A variants, while the cancer risk is less clear. Colon cancer, and other cancer types, have been observed in BMPR1A carriers with JPS and one study reported that cancer was observed in 8.5% of JPS patients (PMID: 32398773). LOH has been studied in some occasions, with LOH reported in around half of polyps from BMPR1A variant carriers (PMID: 26171675). The mechanism of pathogenicity appears to be LOF. This gene-disease association is also supported by animal models and in vitro functional reporter assays (5 points). Reporter assays in cell lines (non-patient) indicated that multiple missense variants, previously reported in patients, decreased membrane localization of the resulting gene product (PMID: 23433720). While complete null mice are embryonic lethal, multiple murine models of (intestinal specific) conditional BMPR1A deletion showed intestinal hyperplasia and gastrointestinal polyps. A variety of gastrointestinal specific BMPR1A conditional mouse models also develop phenotypes consistent with JPS, specifically multiple gastrointestinal polyps (PMIDs: 26773796, 27856416, 15378062). In summary, BMPR1A is definitively associated with Autosomal Dominant Juvenile Polyposis Syndrome.
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