BMPR2 was first reported in relation to autosomal dominant congenital heart disease in 2016 (Liu et al., PMID: 27002414; Sicko et al., PMID: 27788187). Another publication in 2012 reported a paternally inherited deletion at 2q33.1 of about 34 kb, falling into the first intron of the BMPR2 (PMID: 21457232). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, congenital heart disease, Ebstein anomaly, and conotruncal defects have been lumped into one disease entity. One proband with a noncanonical splice-site variant is included in this curation (PMID: 27002414). At least eight other unique variants (missense, frameshifts, splice site) reported in five probands in five publications were not scored due to their high minor allele frequency (> 0.00001) in gnomAD v2.1.1 or a low REVEL score (PMIDs: 27788187, 27002414, 28991257, 33448881, 35910219). The gene-disease relationship is supported by two mouse models and expression data (PMIDs: 23352489, 12441304, 19409885). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Of note, BMPR2 has been classified as definitive for autosomal dominant pulmonary arterial hypertension by the Pulmonary Hypertension GCEP in December 2020. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 9/11/2023 (SOP Version 9).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. The GenCC does not independently verify the submitted information. Though the information is obtained from sources believed to be reliable, no warranty, expressed or implied, is made regarding accuracy, adequacy, completeness, reliability or usefulness of any information. This disclaimer applies to both isolated and aggregate uses of the information. The information is provided on an "as is" basis, collected through periodic submission and therefore may not represent the most up-to-date information from the submitters. If you have questions about the medical relevance of information contained on this website, please see a healthcare professional; if you have questions about specific gene-disease claims, please contact the relevant sources; and if you have questions about the representation of the data on this website, please contact gencc@thegencc.org.