Submission Details

BMP4 was first reported in relation to autosomal dominant BMP4-related ocular growth disorder in 2008 (Bakrania P et al., PMID:18252212). Affected individuals present with a variety of symptoms including microphthalmia and other ocular features, and syndromic symptoms such as brain and digit abnormalities. At least 12 unique variants, mostly nonsense and frameshift, have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data.

Variants in BMP4 have been reported in individuals with the following disease entities: syndromic microphthalmia (OMIM:607932), orofacial cleft (OMIM:600625), and in the literature renal dysplasia has also been asserted. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism between cases with ocular features. Therefore, all cases with ocular features, meaning some of the renal dysplasia reports and all of the syndromic microphthalmia reports, into one disease entity entitled BMP4-related ocular growth disorder. The mechanism for disease appears to be heterozygous loss of function causing a range of phenotypes via variable expressivity (PMID: 21340693).

This gene-disease relationship is supported by several mouse models and expression studies. Mouse models showed that disruption of the BMP4 gene result in craniofacial defects, cystic kidneys, anormal male accessory glands, defective lens morphology and digit abnormalities, such as polydactyly; all of these features are also observed in humans with loss-of-function variants in BMP4 (PMIDs:9851982, 19229034, 9268572). Introduction of beads carrying BMP4 protein rescued the improper lens induction phenotype in one report (PMID:9851982). BMP4 was demonstrated by expression studies to be expressed in the relevant tissues to the phenotype: brain, eye and hand (PMID:18252212).

Variants in this gene have been reported in at least 10 probands in 6 publications (PMIDs:30568244, 21340693, 3492645, 31120642, 18252212, 31053785). Variants in this gene segregated with disease in 8 additional family members. More unscorable evidence is available in the literature.

In summary, there is definitive evidence to support the relationship between BMP4 and autosomal dominant BMP4-related ocular growth disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.

This classification was approved by the ClinGen Glaucoma and Neuro-Ophthalmology Gene Curation Expert Panel on the meeting date 20 February 2025 (SOP Version 11).