BMPR1A – Hereditary Mixed Polyposis Syndrome

Hereditary Mixed Polyposis Syndrome (HMPS) is a rare autosomal dominant condition characterized by mixed histology colorectal polyps, including adenomas, hyperplastic polyps, and juvenile-like polyps, with an elevated lifetime risk of colorectal cancer. Germline mutations in BMPR1A disrupt transforming growth factor-beta (TGF-β) signaling, leading to aberrant colonic epithelial proliferation and mixed polyp formation. Clinical diagnosis relies on endoscopic findings and family history, while molecular confirmation guides surveillance and early intervention strategies.

The causal role of BMPR1A in HMPS was first established by genome-wide linkage in a three-generation Irish kindred (LOD 4.6) and confirmed in a second family, mapping to 10q23.1–10q23.31 with co-segregation of an 11 bp deletion in BMPR1A (PMID:16525031). Subsequent mutation screening in a large cohort of 32 individuals from two families validated loss-of-function variants (c.127_137del (p.Lys43fs)) as disease-causing, demonstrating autosomal dominant transmission and complete penetrance by mid-adulthood.

Independent case reports have reinforced this association. An Irish pedigree harbored a frameshift insertion, c.115_116insA (p.Ser39fs), in BMPR1A with co-segregation in multiple affected members (PMID:19438883). A Japanese family exhibited a germline c.72_73delGA variant with three additional affected relatives over two generations, confirming segregation across ethnicities (PMID:32378721).

A multi-center study of eight Singapore Chinese HMPS families identified BMPR1A defects in four unrelated pedigrees, with germline variants co-segregating with mixed polyposis phenotypes and elevated colorectal cancer incidence (75%) across three generations (PMID:19773747). These findings underscore a consistent autosomal dominant inheritance pattern and a spectrum of loss-of-function mutations.

Variant spectrum in HMPS includes small insertions/deletions causing frameshifts (c.115_116insA (p.Ser39fs); c.127_137del (p.Lys43fs)), single-nucleotide indels, and exon deletions. All reported pathogenic alleles result in truncated protein lacking the kinase domain, supporting haploinsufficiency as the primary mechanism. Population screening has not identified recurrent founder alleles, indicating diverse private variants.

Functional studies reveal that BMPR1A loss impairs BMP signaling, disrupts Smad1/5/8 phosphorylation, and initiates a mixed polyposis-carcinoma sequence in colonic epithelium. In vitro assays demonstrate reduced ligand binding and downstream transcriptional activity for frameshift mutants, concordant with the human phenotype and tumorigenic sequence.

Collectively, genetic linkage, multiple unrelated pedigrees, segregation data, and functional concordance provide Strong clinical validity for BMPR1A in HMPS. Genetic testing for BMPR1A should be offered to individuals with mixed colonic polyps and a family history of HMPS. Early identification of mutation carriers enables tailored endoscopic surveillance and cancer risk management.

References

• Journal of medical genetics • 2006 • Mapping of hereditary mixed polyposis syndrome (HMPS) to chromosome 10q23 by genomewide high-density single nucleotide polymorphism (SNP) scan and identification of BMPR1A loss of function. PMID:16525031
• Colorectal disease : the official journal of the Association of Coloproctology of Great Britain and Ireland • 2010 • Hereditary mixed polyposis syndrome due to a BMPR1A mutation. PMID:19438883
• Japanese journal of clinical oncology • 2020 • A novel germline BMPR1A variant (c.72_73delGA) in a Japanese family with hereditary mixed polyposis syndrome. PMID:32378721
• The American journal of gastroenterology • 2009 • Germline bone morphogenesis protein receptor 1A mutation causes colorectal tumorigenesis in hereditary mixed polyposis syndrome. PMID:19773747

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