Among Diverse Populations with Inherited Retinal Disease, a Genomic Study Reveals

An international team of researchers led by scientists from the University of California San Diego and the Shiley Eye Institute at UC San Diego Health has improved our understanding of how inherited retinal dystrophies (IRDs) affect different populations of people and identified new gene variants that may cause the diseases in the process.

The findings were published in the October 18, 2021 issue of PLOS Genetics.

The retina is a thin layer of tissue in the back of the eye that includes millions of light-sensitive cells (rods and cones). The retina’s principal purpose is to receive, organize, and transmit visual information to our brain via the optic nerve.

IRDs are a category of illnesses that cause gradual vision loss, even blindness, ranging from retinitis pigmentosa to choroideremia. Each IRD is caused by at least one gene mutation, while distinct IRD diagnoses might result from mutations in the same gene.

IRDs are uncommon, yet they affect people of all ages and proceed at varied rates, even among families that have the same disease. Finding the genetic abnormalities that cause the disease is essential for a precise diagnosis.

Any component of the retina might be damaged by retinal disorders. Retinal illnesses that go untreated can cause serious vision loss and perhaps blindness. Some retinal illnesses can be treated with early discovery, while others can be managed or slowed to preserve or even recover eyesight.

The study also highlighted the sorts of mutations that contribute to inherited retinal dystrophies and discovered a substantial number of new IRD causal mutations that were particular to the groups analyzed.

Gene therapy for one form of IRD involving the gene RPE65 has been licensed by the US Foods and Drug Administration, but there are no cures or therapies proven to reduce disease progression for the other IRDs caused by mutations in more than 280 other genes.

The researchers sequenced the complete genomes of 409 people from 108 different family lines, all of whom had previously been diagnosed with IRD. Whole-genome sequences (WGS) is a technique for determining an individual’s whole (or nearly complete) DNA sequence.

It gives a complete picture of a person’s full genome, including mutations and variations, which may be compared to other people’s genomes.

Participants in the study came from three different countries: Mexico, Pakistan, and European Americans in the United States. Blood samples from all subjects were used to undertake genomic analysis, which identified causal variations in 62 of the 108 lineages.

The 62 families contained a total of 94 gene variations, 52 of which had previously been recognized as causal and 42 of which had not. Surprisingly, more than half of the novel variants were not found in the Genome Aggregation Database, a global database of genomic information.

Overall, causal mutations were found in 63% of Mexican participants, 60% of Pakistani participants, and 48% of European American participants.

The study also highlighted the sorts of mutations that contribute to inherited retinal dystrophies and discovered a substantial number of new IRD causal mutations that were particular to the groups analyzed.

Atypical or unexpected alterations in the genome were found in about 13% of the families. Five of the family lineages had mutations in multiple genes in all affected members; one family had mutations in multiple genes in distinct affected members, and one patient had a de novo mutation not seen in both parents.

A further 8% of families exhibited substantial abnormalities in their genome structure that caused inherited retinal illness, and the initial clinical diagnosis in four families was reclassified based on their genotype.

The new findings, according to the authors, improve understanding of the distribution of IRD causal mutations in these three populations, which will help researchers better understand disease variance and presentation. As a result, more efficient genetic testing procedures and medicines for worldwide populations will be developed.

The research team was led by Radha Ayyagari, PhD, professor of ophthalmology and pathology, and Kelly A. Frazer, PhD, professor of pediatrics and director of the Institute for Genomic Medicine, both at UC San Diego School of Medicine; and S. Amer Riazuddin, PhD, associate professor of ophthalmology at John Hopkins University, in collaboration with institutions in India, Mexico, Canada, Brazil, Pakistan and the United States.