• 2
    Haplo
    Score
  • 0
    Triplo
    Score

Gene Facts External Data Attribution

HGNC Symbol
BMP4 (HGNC:1071) HGNC Entrez Ensembl OMIM UCSC Uniprot GeneReviews LOVD LSDB ClinVar
HGNC Name
bone morphogenetic protein 4
Gene type
protein-coding gene
Locus type
gene with protein product
Previous symbols
BMP2B
Alias symbols
No aliases found
%HI
0.22(Read more about the DECIPHER Haploinsufficiency Index)
pLI
0.96(Read more about gnomAD pLI score)
LOEUF
0.33(Read more about gnomAD LOEUF score)
Cytoband
14q22.2
Genomic Coordinates
GRCh37/hg19: chr14:54416454-54423609 NCBI Ensembl UCSC
GRCh38/hg38: chr14:53949736-53956891 NCBI Ensembl UCSC
MANE Select Transcript
NM_001202.6 ENST00000245451.9 (Read more about MANE Select)
Function
Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis (PubMed:31363885). Acts in concert with PTHLH/PTHRP to stimulate ductal outgrowth during embryonic mammary development and to inhibit hair follicle induction (By similarity). Initiates the canonical BMP signaling cascade by associating with type I receptor BMPR1A and type II receptor BMPR2 (PubMed:25868050, PubMed:800600... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

Dosage ID:
ISCA-32810
Curation Status:
Complete
Issue Type:
Dosage Curation - Gene
Haploinsufficiency:
Emerging Evidence for Haploinsufficiency (2)
Triplosensitivity:
No Evidence for Triplosensitivity (0)
Assoc. with Reduced Penetrance:
Yes
Bakrania (2008) and Reis (2011) describe family members with an inherited BMP4 LOF variant but with a reduced severity phenotype. See PMID descriptions for additional information.
Last Evaluated:
11/09/2021

Haploinsufficiency (HI) Score Details

HI Score:
2
HI Evidence Strength:
Emerging Evidence for Haploinsufficiency (Disclaimer)
HI Disease:
  • Microphthalmia with Brain and Digit Anomalies Monarch
HI Evidence:
  • PUBMED: 21340693
    Reis (2011) screened 133 patients with various ocular disorders by chromosomal microarray and Sanger sequencing of BMP4. Five (4 unrelated) of these individuals were found to have variants involving BMP4. One individual with Rieger anomaly, congenital glaucoma, microcornea and nystagmus was found to have a large, 2.3 kb deletion involving BMP4 and thirteen other genes. One patient with anophthalmia/microphthalmia, diaphragmatic hernia, facial asymmetry, and hydrocephalus was found to have a de novo nonsense variant, c.592C>T (p.R198X). This variant was previously reported in a patient with orofacial clefting, other features not reported (Suzuki, 2009). Two maternal half-siblings with anophthalmia, polydactyly, and other anomalies were found to have a frameshift variant, c.171dupC (p.E58RfsX17). This was inherited from the mother who was unaffected, although without a formal ophthalmologic examination. Grandparental studies showed variant to have arisen de novo in the mother. Of note, one of the affected half-siblings also has a second missense variant in BMP4 in trans. One patient with microphthalmia, intellectual disability, and dysmorphic facial features was found to have a deletion affecting BMP4 alone. No inheritance studies were performed.
  • PUBMED: 18252212
    Bakrania (2008): 215 clinical cases with various ocular malformations, including microphthalmia, anophthalmia, and coloboma were screened for "cytogenetic defects by chromosome analysis, gene deletions by MLPA, and mutations in the BMP4 gene by direct sequencing." Two of the 215 individuals had de novo, cytogenetically visible 14q22q23 deletions involving BMP4 and OTX2, another gene thought to be involved in syndromic microphthalmia. Additionally, 18/215 patients had BMP4 sequence variants, though only 14 are described in detail by the authors. Of these, one case (#3) with ophthalmologic abnormalities, CNS anomalies and polydactyly was found to have a BMP4 frameshift (c.226del2, p.S76fs104X) segregating through three additional family members (mother, maternal grandmother, maternal aunt) across three generations, although other family members had less severe ocular phenotype (high myopia). The affected grandmother was also noted to have polydactyly. The other reported patients had either missense variants or deep intronic variants thought to affect splicing based on conservation, though no functional data was presented. Of note, some of these individuals were also found to have variants in HH signaling genes, such as SHH or PTCH1. The authors suggested that these cases could represent "low penetrant variants," suggestive of an interaction between the two pathways.
  • PUBMED: 31053785
    Blackburn (2018) presents 3 clinical cases that do not have clinically apparent microphthalmia or anopthalmia. Case 1 presented with developmental delay, macrocephaly and polydactyly. WES detected a de novo BMP4 nonsense variant, c.1052C>G p.(Ser351*). Case 2 presented with ocular anomalies (sclerocornea), facial dysmorphism, polydactyly and syndactyly. Case 3 presented with developmental delay, intellectual disability, arachnodactyly. Both cases had large de novo deletions (microarray) involving BMP4 and many other genes. Case 3 also had a de novo Koolen de Vries deletion. Blackburn then reviews 14 LOF BMP4 variants (in 27 individuals) reported previously and in this paper, and notes that microphthalmia is the most commonly observed eye-finding but with variable severity, even within families. Blackburn concludes that BMP4 is an important developmental gene but associated clinical phenotypes require further elucidation.
HI Evidence Comments:
Variants in BMP4 have been observed in individuals with varying phenotypes, including ocular findings (microphthalmia, anophthalmia, etc.), facial clefting, genitourinary malformations, digital abnormalities (polydactyly, syndactyly, brachydactyly), and/or developmental delays. Large deletions including BMP4 and other genes have been reported in patients with anophthalmia/microphthalmia; however, most of these also include OTX2, which is also associated with microphthalmia. Mouse studies have shown that Bmp4 is critical in dorsoventral patterning of the optic vesicle and Bmp4 +/− heterozygous mice have a variety of eye defects; however, the penetrance and severity of the ocular phenotype can be influenced by the background strain (PMID 19116164). Additional nonsense BMP4 variants have been reported for Stickler syndrome (1 case, PMID 30568244), Mayer-Rokitansky-Küster-Hauser syndrome (2 cases, PMID 33434492), combined pituitary hormone deficiency (1 case, PMID 31120642), and colorectal cancer (1 case, PMID 20949628).

Triplosensitivity (TS) Score Details

TS Score:
0
TS Evidence Strength:
No Evidence for Triplosensitivity (Disclaimer)

Genomic View

Select assembly: (NC_000014.8) (NC_000014.9)