Genetic findings of individuals with inherited retinal diseases in Finland

Abstract

Genetic research can benefit from population isolates like Finland, as they tend to have a high concentration of deleterious alleles on a small number of low‐frequency variants. To investigate gene findings from the patients with inherited retinal disorders (IRD) in Finland, retrospectively collected data from the patients with IRDs treated between January 1st of 2012, and December 31st of 2020 at the Department of Ophthalmology, Helsinki University Hospital. Of the 638 patients that underwent genetic testing, 79% received a likely genetic diagnosis (504/638). The genetic findings corresponded to autosomal recessive (AR) inheritance in 242 patients, X‐linked (XL) in 158, autosomal dominant (AD) in 94, and mitochondrial inheritance in 22 patients. The most common genetic diagnosis was X‐linked retinoschisis as 17% (84/504) harboured pathogenic variants in RS1. The most common retinitis pigmentosa genes with causative variants were CERKL (8.5%, 43/504), RPGR (5.8%, 24/504), and EYS (5%, 25/504). CERKL variant c.375C>G, p.(Cys125Trp) and EYS c.1155T>A, p.(Cys385Ter) are frequent founder mutations. The Stargardt disease is less common than in other Western countries, the pathogenic variants in the ABCA4 gene were found in 24 patients. Pathogenic variants were also found in CHM (26), and CLRN1 (16). The genetic landscape of IRDs in Finland differs from other Western countries due to its specific isolated population history. The high yield of genetic findings is possibly explained by the enriched founder mutations in the population. One‐fifth of the patients are lacking genetic diagnosis, which might be due to shortages in the testing methods, i.e., non‐coding variants and complex structural genomic variants are missing. To address this problem, we have been utilizing the whole genome and long‐read sequencing methods to uncover new pathogenic variants. In two families with IRDs, we have found large structural variants in the RP1 and PRPH2 genes using Nanopore long‐read sequencing. In the future, we try to utilize the advantages of the population isolate to find unknown genes causing IRDs.