Neovascular age-related macular degeneration in two Saudi siblings: a familial phenotype-exome analysis of shared retinal variants and AMD-associated SNPs

Age-related macular degeneration (AMD) is a multifactorial disease influenced by aging, environmental factors, and genetic susceptibility. We performed a phenotype-exome analysis of two siblings with neovascular AMD to characterize their macula-variant profile. Two elderly Saudi siblings with neovascular AMD were identified through an institutional AMD genetics study conducted at a tertiary-academic care center. Diagnosis was established by retina consultants using comprehensive ophthalmic examination and multimodal imaging. Whole-exome sequencing variants were filtered to retain rare coding and splice-site variants (allele frequency < 0.01) shared by both affected siblings. Three complementary approaches were applied: filtering for AMD-associated genes, retina-relevant genes, and previously reported AMD-associated SNPs in Middle Eastern populations. Both siblings had bilateral neovascular AMD with chronic macular remodeling. Sibling S1, diagnosed at age 72, showed bilateral scarred/inactive choroidal neovascularization on later follow-up. S2, diagnosed at age 75, showed a more active right-eye exudative phenotype earlier in the imaging series and later bilateral structural macular phenotype. Rare shared variants were identified across AMD-associated and retina-relevant genes. A rare heterozygous HMCN1 p.Asn2980Thr variant associated with AMD was detected in both siblings. Additional variants were identified in RP1L1, MYO7A, CEP164, CDH3, ZNF513, and FLVCR1, alongside previously reported Middle Eastern AMD-associated SNPs in CFH, APOE, ARMS2, MTHFR, and F5. The shared phenotypic-genotypic features support familial aggregation of neovascular AMD. The coexistence of AMD-associated, retina-related, and previously reported risk variants suggests a potentially oligogenic and multifactorial genetic architecture underlying neovascular-AMD disease susceptibility.