October 2021

International effort identified new and different causative gene variants for a group of
diseases that can lead to severe vision loss or blindness

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

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

IRDs are a group of diseases, from retinitis pigmentosa to choroideremia, that result in
progressive vision loss, even blindness. Each IRD is caused by at least one gene
mutation, though mutations in the same gene may lead to different IRD diagnoses.

IRDs are rare, but they affect individuals of all ages, progressing at different rates, even
within families afflicted with the same disease. Specific diagnosis depends on finding
the genetic causative mutations.

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

The researchers conducted whole-genome sequences (WGS) of 409 persons from 108
unrelated family lineages, each with a previously diagnosed IRD. WGS is a process of
determining the entirety, or near-entirety, of the DNA sequence of an individual. It
provides a comprehensive portrait of the person’s entire genome, including mutations
and variants, which can be used for broad comparative purposes.

Study participants were recruited from three different geographic regions: Mexico,
Pakistan and European Americans living in the United States. Genomic analyses were
conducted from blood samples taken from all participants, which revealed causative
variants in 62 of the 108 lineages. A total of 94 gene variants were found in the 62
families: 52 variants had previously been identified as causative and 42 had not.
Surprisingly, more than half of the new variants were not listed in the Genome
Aggregation Database, an international compilation of genomic data.

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

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. 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.

An additional 8 percent of families had large changes in the structure of their genome
causing the inherited retinal disease and the initial clinical diagnosis in four families was
re-classified based on their genotype.

The authors said the new findings boost understanding of the distribution of IRD
causative mutations in these three diverse populations, which will further understanding
of disease variation and presentation. That, in turn, will help design more efficient
genetic testing strategies and therapies applicable to global populations.

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.

Co-authors include: Pooja Biswas, UC San Diego and REVA University, India; Adda L.
Villanueva, Retina and Genomics Institute, Mexico and Hôpital Maisonneuve Rosemont,
Canada; Angel Soto-Hermida, Hiroko Matsui, Shyamanga Borooah, Berzhan Kumarov,
Bonnie Huang, John Suk, Jason Zhao, Sindhu Devalaraja, Andrew Huynh, Akhila
Alapati and Qais Zawaydeh, UC San Diego; Jacque L. Duncan, UCSF; Gabriele
Richard, GeneDx; Shahid Yar Khan, Johns Hopkins University School of Medicine; Kari
Branham, Naheed W. Khan and John R Heckenlively, University of Michigan; Benjamin
Bakall, University of Arizona; Jeffrey L. Goldberg, Byers Eye Institute; Luis Gabriel,
Genetics and Ophthalmology, Genelabor, Brazil; Pongali B Raghavendra, REVA
University and Manipal University, Brazil India; Richard G Weleber, Oregon Health &
Science University; J. Fielding Hejtmancik, National Institutes of Health; Sheikh
Riazuddin, University of Punjab and Allama Iqbal Medical College, Pakistan; and Paul
A. Sieving, National Eye Institute and UC Davis.

Funding for this research came, in part, from the National Institutes of Health (grants
EY031663, EY13198, EY21237, EY002162 and P30EY022589) the Foundation
Fighting Blindness; Research to Prevent Blindness; The Claire Giannini Foundation;
The L.L. Hillblom Foundation and That Man May See, Inc.

Full study:
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009848

Media contact: Scott LaFee, 858-249-0456, slafee@health.ucsd.edu