A GWAS using the FinnGen cohort (540 IRD cases, 473,945 controls) was performed to discover novel genes linked to inherited retinal disease (IRD), with replication in a Finnish clinical cohort (n=49) and a UK cohort (n=2), conducted January 2024–December 2025.
13 recessive loci reached genome-wide significance (P < 5×10⁻⁸); 4 were novel IRD associations, including *XXYLT1* (c.505-1G>C founder variant). In the replication cohort, 5 more homozygous individuals (4 families) were identified; phenotype was cone-rod or macular dystrophy with cystoid macular edema and/or schisis-like changes. RNA sequencing confirmed exon 2 skipping and loss-of-function. Two UK patients carried a distinct homozygous *XXYLT1* missense variant (c.766G>A, p.Glu256Lys).
- Case numbers are small (540 GWAS cases; 7 total replication cases), limiting statistical power for rare variants. - Founder population (Finnish) may limit generalizability of the c.505-1G>C variant to other ethnicities. - Functional studies were RNA-based; no protein-level or animal model validation was reported.
Clinicians evaluating unsolved IRD cases — especially cone-rod or macular dystrophy with cystoid macular edema or schisis-like findings — should consider adding *XXYLT1* to diagnostic gene panels. GWAS in founder populations is a viable strategy for uncovering rare Mendelian disease genes.
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