ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000010.10) (NC_000010.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11381269 Howe et al. (2001) identified four BMPR1A germline truncation pathogenic variants in four juvenile polyposis kindreds. Genomic sequencing of BMPR1A in each of these juvenile polyposis kindreds disclosed these truncation pathogenic variants in all affected kindred members but not in normal individuals (figure 2). Individual Case Evidence: Segregation Among Similarly Affected Family Members ? NM_004329.2(BMPR1A):c.44_47delTGTT (p.Leu15Serfs) ? NM_004329.2(BMPR1A):c.715C>T (p.Gln239Ter) ? NM_004329.2(BMPR1A):c.812G>A (p.Trp271Ter) ? NM_004329.2(BMPR1A):c.961del (p.Phe320_Leu321insTer)
15235019 Howe et al (2004) performed a large cohort study including a total of 77 Juvenile polyposis (JP) cases. Germline BMPR1A gene pathogenic variants were identified in 16 cases (20.8%). These included ten truncation (including nonsense and deletion) variants and six missense mutations. Individual Case Evidence: Unknown Inheritance, total 10 cases
23399955 Ngeow et al (2013) performed a large prospective, referral-based study of 603 patients with moderate-load colorectal polyps. Twenty cases (3.3%) were identified carrying a BMPR1A pathogenic variants including twelve BMPR1A focal deletion and/or truncation variants and eight misssense variatns. All the BMPR1A pathogenic variants carriers were diagnosed with Juvenile polyposis and/or other types of cancers (supplementary table). Individual Case Evidence: Unknown Inheritance, total 12 cases

Haploinsufficiency phenotype comments:

BMPR1A is a type I receptor of the TGF-? superfamily, with a cysteine-rich extracellular region, an intracellular glycine?serinerich (GS) domain near the plasma membrane and an intracellular kinase domain. Loss of function pathogenic variants have been associated with Juvenile polyposis syndrome, an autosomal dominant condition that predisposes gene carriers to various types of tumors (see GeneReviews for additional information . As described above, Howe et al. (2001) first identified four BMPR1A germline truncation pathogenic variants in four juvenile polyposis kindreds. Further sequencing indicated the pathogenic variants were inherited and segregated with disease in these four families. Afterwards, many case reports and cohort studies further supported and provided additional evidence for the association between BMPR1A haploinsufficiency and Juvenile polyposis syndrome (PMID: 11381269, 15235019, 23399955). Other supporting evidence for BMPR1A haploinsufficiency includes but is not limited to: ? Zhou et al. (2001) PubMed: 11536076 ? Cao et al. (2006) PubMed: 16525031 ? O'Riordan et al (2009) PMID: 19438883 ? Gao et al. (2020) PMID: 32487124

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

There are currently no reports of focal duplications involving only BMPR1A, therefore the current triplosensitivity score is 0.