**Background:** Focal and segmental glomerulosclerosis (FSGS) is a histopathological diagnosis characterized by sclerosis of less than half the glomerular tuft in fewer than half the glomeruli. FSGS is classified into primary (autoimmune), secondary (hyperfiltration), and genetic forms. Genetic FSGS often presents with lower proteinuria, is steroid-resistant, and does not recur after transplantation. More than 70 genes have been implicated, with inheritance patterns including autosomal recessive (common in children), autosomal dominant (common in adults), X-linked, and mitochondrial. Ocular abnormalities are particularly common in genetic kidney disease due to shared developmental, structural, and physiological similarities between the kidney and eye. This review aimed to characterize the ocular associations of individual genes affected in FSGS to help indicate an underlying genetic disorder and, in some cases, the specific gene involved.
**Methods:** Genes for FSGS were downloaded from the Genomics England Renal Proteinuria panel (v2.77, green and amber genes) in October 2020. A systematic literature search was performed in Medline (OVID), Embase, and the Cochrane Database of Systematic Reviews using terms (eye* or ocular or retina* or lens or cornea* or vision or ophthalm*) combined with each gene name. All English-language manuscripts likely to include ocular manifestations were reviewed. Full-text articles not reporting FSGS or ocular findings, or those only available as abstracts or conference proceedings, were excluded. Additional references were hand-searched, and Online Mendelian Inheritance in Man (OMIM) was used to identify renal, extra-renal, and further ocular features in October 2022. The Human Protein Atlas was examined for retinal mRNA expression, and the Mouse Genome Informatics database was examined for ocular phenotypes in mouse models. Genes associated with secondary FSGS (CLCN5, OCRL, CUBN, PAX2) and common FSGS-associated mitochondrial diseases (MELAS, MIDD, Kearns-Sayre syndrome) were also searched.
**Key Results:** From 4702 records identified, 303 were included after screening and full-text review. Fifty-five genes from the Genomics England Renal proteinuria panel were studied. Thirty-two (58%) had ocular manifestations reported in human disease. Most genes commonly associated with congenital nephrotic syndrome (NPHS1, NPHS2, WT1, LAMB2, PAX2, PLCE1) and many genes associated with childhood-adolescent FSGS (NPHS1, NPHS2, WT1, LAMB2, SMARCAL1, NUP107, PLCE1) had ocular abnormalities. The commonest adult-onset FSGS genes (COL4A3, COL4A4, COL4A5) and GLA (Fabry disease) also had ocular features, but ACTN4, CD2AP, INF2, and TRPC6 did not. Of the 55 genes, 51 (93%) had transcripts expressed in the retina, but only 16 (29%) had more than 10 transcripts per million. Twenty-seven genes (49%) were associated with an ocular phenotype in a mouse model. A further 12 genes (22%) had either >10 transcripts per million in the retina or an ocular phenotype in a mouse model, suggesting potential unrecognized ocular features. The most common ocular manifestations across multiple genes were ptosis, myopia, strabismus, cataract, retinal atrophy, and inherited retinal degeneration. Highly specific gene-ocular associations included: Pierson syndrome (LAMB2) with microphthalmia; papillorenal syndrome (PAX2) with optic disc coloboma; WAGR syndrome (WT1) with aniridia; Alport syndrome (COL4A3, COL4A4, COL4A5) with anterior lenticonus, fleck retinopathy, temporal retinal thinning, maculopathy, and macular hole; and Fabry disease (GLA) with corneal verticillata and tortuous retinal vessels. Mitochondrial diseases (MELAS, MIDD, Kearns-Sayre) typically caused inherited retinal degeneration and retinal atrophy.
**Clinical Implications:** The presence of ocular abnormalities in a patient with FSGS strongly suggests a genetic basis and should prompt genetic testing. Specific ocular findings can point to a particular gene, enabling a precise diagnosis. For example, anterior lenticonus is pathognomonic for Alport syndrome, and corneal verticillata is highly specific for Fabry disease (after excluding pharmacological causes). Ocular features may also indicate more severe kidney disease: in Pierson syndrome, severe ocular phenotypes are associated with earlier onset kidney failure; in Alport syndrome, more severe genetic variants are associated with lenticonus, more severe retinopathy, and earlier kidney failure; in Fabry disease, retinal and conjunctival vessel tortuosity correlates with a more rapid decline in kidney and cardiac function. Some ocular abnormalities (e.g., coloboma, optic atrophy) are obvious to the renal physician and warrant a family history and genetic testing. Even non-progressive congenital abnormalities can develop complications such as strabismus, cataract, glaucoma, and retinal detachment, requiring ophthalmologic monitoring and treatment. The study's strengths include the systematic approach using a widely used gene panel, OMIM, literature review, retinal expression data, and mouse models. Limitations include the panel not including all possible FSGS genes, rare reports with incomplete ophthalmic examinations, and limited data on the age-dependent prevalence of ocular features. In conclusion, ocular abnormalities are common in genetic forms of FSGS, aid in diagnosis, and may predict renal disease severity, and some require monitoring and treatment to preserve vision.