Shared retinal variants point to familial clustering of neovascular macular degeneration in two Saudi siblings

Two elderly Saudi siblings who both developed neovascular age-related macular degeneration carried a shared set of rare retinal variants and known AMD-associated genetic risk markers, according to a phenotype-exome analysis published in BMC Ophthalmology. The siblings were identified through an institutional AMD genetics study conducted at a tertiary academic care center, and a phenotype-exome analysis was performed to characterize their macula-variant profile.

Diagnosis was established by retina consultants using comprehensive ophthalmic examination and multimodal imaging. Each had bilateral neovascular AMD with chronic macular remodeling. Sibling S1 was diagnosed at age 72, and later follow-up showed bilateral scarred or inactive choroidal neovascularization. Sibling S2 was diagnosed at age 75 and displayed a more active exudative phenotype in the right eye earlier in the imaging series, later progressing to a bilateral structural macular phenotype.

Whole-exome sequencing variants were filtered to retain rare coding and splice-site variants with an allele frequency below 0.01 that were shared by both affected siblings. Three complementary filtering approaches were then applied: filtering for AMD-associated genes, retina-relevant genes, and previously reported AMD-associated SNPs in Middle Eastern populations.

The analysis identified rare shared variants across both AMD-associated and retina-relevant genes. A notable finding was a rare heterozygous variant in the HMCN1 gene, p.Asn2980Thr, that has been associated with AMD and was detected in both siblings.

Beyond HMCN1, the siblings shared additional rare variants in several retina-relevant genes, including RP1L1, MYO7A, CEP164, CDH3, ZNF513, and FLVCR1.

The siblings also carried previously reported Middle Eastern AMD-associated SNPs in established susceptibility genes and loci: CFH, APOE, ARMS2, MTHFR, and F5. Their co-occurrence in both siblings is consistent with the known multifactorial genetic architecture of AMD.

The authors concluded that the shared phenotypic and genotypic features support familial aggregation of neovascular AMD in this family. They proposed that the coexistence of AMD-associated variants, retina-related variants, and previously reported Middle Eastern risk SNPs suggests a potentially oligogenic and multifactorial genetic architecture underlying susceptibility to neovascular AMD, meaning that multiple variants acting together, rather than a single gene, may shape disease risk.

As a two-person familial case analysis, the study cannot establish that any individual variant caused disease, and the identified variants were not functionally validated. AMD is known to be influenced by aging, environmental factors, and genetic susceptibility, and the findings should be viewed as hypothesis-generating.

Subject of Research: Familial phenotype-exome analysis of shared retinal variants and AMD-associated SNPs in two Saudi siblings with neovascular age-related macular degeneration

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

Article References: Sannan, N. S., Alqahtani, A. S., Talaat, K., Alhalwani, A. Y., Alharthi, A., Alghamdi, Y. M., Fallatah, O., Alotaibi, M. A., Al Marwani, S., Mahdali, K., Qawas, M., Asel, T., Abdulkareem, A. A., & Almuzaini, B. (2026). Neovascular age-related macular degeneration in two Saudi siblings: a familial phenotype-exome analysis of shared retinal variants and AMD-associated SNPs. BMC Ophthalmology. https://doi.org/10.1186/s12886-026-05461-w

Image Credits: AI Generated

DOI: 10.1186/s12886-026-05461-w

Keywords: age-related macular degeneration, neovascular AMD, whole-exome sequencing, HMCN1, CFH, ARMS2, APOE, Saudi Arabia, familial aggregation, retinal variants, oligogenic inheritance, BMC Ophthalmology