Genomics Study Reveals Variants Behind Inherited Retinal Dystrophies

October 21, 2021 - University of California San Diego and Shiley Eye Institute at UC San Diego Health scientists analyzed how inherited retinal dystrophies (IRDs) impact diverse populations of people. Through the process, researchers also identified new gene variants that could lead to the disease.

IRDs are a group of diseases that result in progressive vision loss and sometimes blindness. Each IRD is caused by at least one gene mutation, though mutations in the same gene could lead to different IRD diagnoses. While IRDs are rare, they impact individuals of all ages and progress at different rates. Specific diagnoses depend on discovering the genetic causative mutations.

The United States Food and Drug Administration approved gene therapy for treating one form of IRD involving the gene RPE65. However, there are no cures or treatments to slow the disease progression of the other IRDs caused by mutations in more than 280 different genes.

The research team conducted whole-genome sequencing of 409 individuals from 108 unrelated families, each previously diagnosed with IRD. The study participants were recruited from three different geographic regions, including Mexico, Pakistan, and European Americans living in the United States.

Genomic analyses were conducted on blood samples from every participant, revealing causative variants in 62 of the 108 lineages. A total of 94 gene variants were discovered in the 62 families: 52 variants had previously been identified as causative and 42 had not. In addition, researchers found that more than half of the new variants were not listed in the Genome Aggregation Database.

Overall, causative variants were found in 63 percent of Mexican participants, 60 percent of Pakistani, and 48 percent of European Americans.

“The study also identified a large proportion of new IRD causative mutations specific to the populations studied and revealed the types of mutations contributing to inherited retinal dystrophies. Approximately 13 percent of the families displayed atypical or unexpected changes in the genome,” the press release stated.

“Five of the family lineages had mutations in more than one gene in all affected individuals; one family carried mutations in different genes in different affected members and a de novo mutation was found in one patient that was not present in both parents.” 

Additionally, 8 percent of families had significant changes in their genomic structure, causing IRD and the initial clinical diagnosis in four families to be re-classified based on their genotype. According to the study authors, the new findings boost the understanding of IRD causative mutation in the three different diverse populations, furthering their understanding of disease variations and presentation.

The information will help researchers develop more effective precision medicine treatments and therapies applicable to global populations.