Case Report: Expanding the LRP5-phenotypic spectrum of the novel c.4462A > G (p.Ser1488Gly) variant with isolated...

LRP5-related retinal disease is classically associated with familial exudative vitreoretinopathy (FEVR), whereas biallelic inactivating variants cause osteoporosis-pseudoglioma syndrome. We report a severe congenital FEVR-like retinal dysplasia in a child carrying the novel heterozygous LRP5 c.4462A > G (p.Ser1488Gly) variant of uncertain significance (VUS), adding carefully documented phenotypic layer to a ClinVar entry that has lacked disease-specific clinical context.

A full-term female infant presented with nystagmus, absent visually directed behavior, and visual responsiveness limited to bright light. Examination under general anesthesia at 15 months revealed bilateral macular pseudocoloboma, mid-peripheral termination of retinal vascularization with avascular far peripheral retina, scattered pigment clumping, and microphthalmia. Optical coherence tomography showed marked outer retinal atrophy with an irregular V-shaped foveal contour, and electroretinography demonstrated non-detectable rod and cone responses. A targeted inherited retinal dystrophy panel identified the heterozygous LRP5 c.4462A > G variant, absent from population databases and classified as a VUS. No pathogenic or likely pathogenic variants were found in other tested genes relevant to FEVR, Norrie disease spectrum, vitreoretinal dysplasia, microphthalmia-associated retinopathy, or early-onset retinal dystrophy. The variant was inherited from an asymptomatic father. No retinal intervention was indicated. Follow-up to 3 years showed no progression and no systemic features of LRP5-related bone disease.

The phenotype is best interpreted as an isolated, atypical FEVR-like congenital retinal dysplasia within LRP5-associated FEVR spectrum. However, paternal inheritance from an unaffected carrier, atypical severity, and lack of functional validation preclude definite causal assignment. This report supports cautious VUS interpretation and adds clinically relevant phenotypic evidence for future reinterpretation of LRP5 p.Ser1488Gly.