Molecular genetic characterization of patients with inherited retinal diseases in Hungary: solving mysteries

Abstract

Purpose : To investigate the genetic etiologies of inherited retinal diseases (IRDs) in Hungary by performing clinical and molecular assessments of a cohort of IRD patients.

Methods : We recruited 94 unrelated IRD families, comprising individuals who had undergone gene-panel screening (33 families) and those who had never been screened (61 families), residing in Hungary. All participants underwent a thorough ophthalmological evaluation. Peripheral blood or saliva samples were collected to extract DNA, which was then subjected to exome sequencing. Genome sequencing was performed for all cases who were negative to this first wave of exome analysis (~5%). A dedicated in silico pipeline for mutation detection was applied to all data.

Results : By combining genome or exome data with precise clinical phenotyping, we achieved molecular diagnoses for 56 out of 94 families (57,14 %). Fifty-three of these cases had pathogenic or likely pathogenic variants in known IRD genes or loci, whereas 3 cases had convincing mutations in novel disease genes, currently under further investigation. In total, we identified 76 disease-causing mutations in 32 different genes, including 20 variants that were not reported before. Notably, the gene ABCA4 carried the highest number of mutations, with a total of 25 distinct pathogenic variants detected in 11 individuals. These mutations were observed either in the homozygous form or in compound heterozygosity with other pathogenic variants. Other genes, such as USH2A, RPGR, EYS, and PCARE (10%, 5%, 3% and 3%, respectively) were also found to be frequently mutated within this cohort.

Conclusions : This study shows that the combination of genome-wide sequencing techniques with a robust computational analysis allows providing molecular diagnosis for cases who were seemingly negative to standard genetic tests. Our results may contribute to better genetic diagnosis and the design of future gene-based therapy in Hungary, as well as neighboring areas in Europe.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.