Submission Details

The LRP5 gene was first reported in relation to osteoporosis-pseudoglioma syndrome in 1996 (Gong et al., PMID: 11719191) and in relation to autosomal recessive cases of familial exudative vitreoretinopathy in 2004 (Jiao et al., PMID: 15346351). Affected individuals with causal biallelic variants in LRP5 have since been identified in a number of other publications, with osteoporosis-pseudoglioma syndrome (MIM#: 259770) describing the subset of cases exhibiting congenital or early childhood onset of blindness caused by ocular defects such as retinal folds, severe retinal detachment, optic disc traction, and abnormal vascular growth including hyaloid vascular remnants in the vitreous body, as well as juvenile onset of osteoporosis, reduced bone mineral density, and recurrent fractures. Additional features of these cases can include microphthalmos, moderate intellectual disability, short stature, joint laxity, and/or hypotonia. The subset of cases diagnosed with familial exudative vitreoretinopathy (MIM#: 601813) generally exhibit early onset of visual problems ranging from peripheral visual disturbances to blindness in some cases, with underlying peripheral retinal avascularity, retinal neovascularization, retinal folds, retinal exudate, vitreoretinal traction, and retinal detachment, as well as reduced bone mineral density and predisposition to fractures. Some of the disease-causing LRP5 variants overlap between cases with different diagnoses. Per criteria outlined by the ClinGen Lumping & Splitting Working Group, we found the molecular mechanism (biallelic loss of function in the LRP5 gene product) and mode of inheritance (autosomal recessive) to be consistent among unrelated patients diagnosed with either osteoporosis-pseudoglioma syndrome (MIM#: 259770) or familial exudative vitreoretinopathy 4 (MIM#: 601813). The phenotypic variability between them appeared to represent a spectrum of disease rather than separate disease entities. Therefore, these cases have been lumped into a single disease entity, referred to as LRP5-related exudative vitreoretinopathy. Additional disease entities, including autosomal dominant familial exudative vitreoretinopathy, have been asserted in relation to monoallelic variants in LRP5. While this phenotype is characterized by some similar clinical characteristics and overlapping variants, its different mode of inheritance and incomplete penetrance have raised the possibility of a different or incompletely characterized mechanism of pathogenesis, including additional unidentified variants in other loci or within LRP5 itself. Thus, LRP5 has been separately curated for its relationship to these other disease entities.

Seventeen suspected disease-causing variants were scored as part of this curation (six missense, three frameshift, six nonsense, one C-terminal deletion, and one affecting splicing), which have been collectively reported in thirteen probands in six publications (PMID: 15346351, PMID: 11719191, PMID: 20034086, PMID: 18602879, PMID: 15981244, PMID: 27228167). Nine probands were homozygous for the variant of interest, eight of whom were reported to have consanguineous parents (PMID: 15346351, PMID: 11719191, PMID: 18602879). The other four probands were compound heterozygotes within the LRP5 locus (PMID: 20034086, PMID: 15981244). The mechanism of pathogenicity appears to be biallelic loss of function, characterized in some cases by nonsense or frameshift variants predicted to trigger absence of the gene product (PMID: 18602879, PMID: 11719191, PMID: 15981244). All probands harboring two predicted null variants have been diagnosed with osteoporosis-pseudoglioma syndrome rather than familial exudative vitreoretinopathy (PMID: 18602879, PMID: 11719191). Three studies showing linkage of the clinical phenotypes to the LRP5 locus were available in these publications (PMID: 8659519, PMID: 15346351, PMID: 18602879), and contributed to the scoring of the gene-disease relationship. More case-level data was available, but was not scored as part of this curation as the maximum scoring for this evidence type had already been reached.

This gene-disease association is also supported by experimental evidence that LRP5 encodes a co-receptor for canonical Wnt signaling (PMID: 11336703), consistent with the known role of this signaling pathway in mediating bone formation (PMID: 23514963). This biochemical function matches that of the FZD4 receptor, which is encoded by a gene in which monoallelic variants cause familial exudative vitreoretinopathy 1, with an autosomal dominant pattern of inheritance (PMID: 12172548). While LRP5 is ubiquitously expressed throughout human tissues, its first expression in embryonic bone coincides with cell differentiation into osteoblasts and the beginning of membranous ossification (PMID: 11719191). A dominant negative C-terminally truncated fragment of LRP5 has been shown to inhibit the bone accrual / thickening of cultured bone explants (PMID: 11719191). Finally, a mouse with biallelic loss-of-function mutations in Lrp5 recapitulates human patient phenotypes including early onset of decreased osteoblast proliferation, reduced bone mineral density, remnants of the hyaloid vascular system, and failure of macrophage-mediated endothelial cell apoptosis (PMID: 11956231).

In summary, LRP5 is definitively associated with LRP5-related exudative vitreoretinopathy. This has been repeatedly demonstrated in both research and diagnostic settings, and has been upheld over time without the emergence of contradictory evidence, leading to a definitive classification. This classification has been approved by the ClinGen Retina GCEP on March 2nd, 2023 (SOP Version 9).