Looking for Genes in All the Right Places

July 20, 2011

An innovative, targeted search technique known as whole-exome sequencing is dramatically reducing the time, effort and expense it takes to discover genetic defects that cause retinal disease. While the increasing raw power of genetic-screening technologies is continually accelerating the pace of gene discoveries, the whole-exome search strategy is a major leap forward.

“Identifying genetic defects is essential to the development of vision-saving treatments and cures for retinal diseases. And while we have found more than 200 disease-causing genes over the last two decades, the process to find each one has taken significant time and effort,” says Stephen Rose, chief research officer, Foundation Fighting Blindness. “Exome sequencing brings our search efficiency to a whole new level, because it focuses on the regions where defects are most likely to occur.”

The whole-exome screening approach targets exons, which are critical regions, because they contain code that tells cells what proteins to make. Proteins are essential to the function and health of all cells, so when a defect in an exon causes a protein to be missing or improperly formed, diseases often occur. Because exons are scattered across only one percent of the six billion pieces of DNA that comprise a person’s complete set of genetic information, the search for defects is narrowed considerably.

A Foundation-funded research team, which included Stephen Daiger, Ph.D., from The University of Texas Health Sciences Center in Houston, and Peter Humphries, Ph.D., from Trinity College in Dublin, Ireland, recently used whole-exome sequencing to identify a defect in the gene RPE65 that is the cause of autosomal dominant retinitis pigmentosa (adRP) in two Irish families.

Results of the study that uncovered RPE65’s link to adRP were published online on June 8, 2011 in the European Journal of Human Genetics.

Scientists have known for 15 years that different defects in RPE65 were a cause of recessive retinitis pigmentosa and Leber congenital amaurosis (LCA), and have even developed a gene therapy that, in clinical trials for that form of LCA, has restored vision in more than 40 children and young adults who were nearly blind. The knowledge gained from the LCA clinical trials is giving scientists a head start in developing a therapy for adRP caused by RPE65.

In another successful whole-exome sequencing effort, an investigative team from the Bascom Palmer Eye Institute at the University of Miami found the genetic defect causing retinitis pigmentosa in three of a family’s four siblings. For 18 years, investigators had been using other approaches to finding the family’s genetic defect for RP, but came up empty. The implicated gene, DHDDS, had not been linked previously to a retinal condition, but researchers are already creating models of this form of disease to develop approaches to treating it.

“What’s exciting about the DHDDS discovery is researchers believe that the gene accounts for retinitis pigmentosa in a significant number of people and families, especially those with Ashkenazi Jewish heritage,” says Dr. Rose. “In fact, in a study funded by the Foundation, Hadassah Medical Center in Jerusalem found that DHDDS affected 20 of their patients. Each new gene identified is a piece to the puzzle. DHDDS happens to be a relatively big piece.”

Results of the studies performed by Bascom Palmer and Hadassah Medical Center were published on February 11, 2011 in The American Journal of Human Genetics.

While whole-exome sequencing is a relatively new approach, Dr. Rose says that virtually all Foundation genetic research centers are either now using it or will be in the near future. He adds, “Given the great results we have seen already, I am optimistic that whole-exome sequencing is going to have a big impact on the pace of gene discovery and the development of new treatments.”