For nearly three years, Troy and Jennifer Stevens struggled to learn the identity of the gene responsible for their son Gavin’s blindness. Although doctors were able to diagnose him with Leber congenital amaurosis – a rare form of inherited childhood blindness – the first round of genetic testing could not pinpoint the defective gene.
But thanks to the determined efforts of genetics expert John Chiang, Ph.D. (then at Casey Eye Institute), and Troy and Jennifer’s tenacity, a new gene linked to Gavin’s severe form of LCA has been discovered using a new, sophisticated approach called whole-exome sequencing. Dr. Chiang, then the director of Casey’s Molecular Diagnostic Laboratory along with collaborators at Beijing Genomics Institute (BGI) published their findings in the medical journal Nature Geneticsin July.
“Uncovering this gene has expanded our understanding of the pathway of retinal diseases like LCA and will help the advancement of gene therapy treatment for Gavin and other patients with this genetic mutation,” notes Dr. Chiang, who joined Casey’s faculty in June of 2011. The gene, identified as NMNAT1, is the 18th linked to LCA, but different than most others in terms of its function and location. “It’s a very important gene on chromosome 1, but you only see its effects in the eye,” he points out.
Jennifer says it was a “mother’s intuition” that sensed something was wrong with her son’s eyesight soon after he was born. After extensive testing and visits with eye specialists, the family was devastated to learn that Gavin, now three, had all the signs of a severe form of LCA. Later, while researching the disease, she learned about a young boy with LCA who regained some vision with gene therapy. Realizing that the first step for gene therapy treatment is identifying the gene mutation, the Stevens sent Gavin’s blood samples to a genetic testing laboratory when he was 14-months old. “We wanted to make things happen,” says Jennifer, who lives in Chino, California with her husband Troy, Gavin and his older brother Landon. Nearly a year later, while attending a conference for families with LCA, the Stevens got the disappointing news that test results were inconclusive. “We were so desperate for an answer and thought, ‘we have to find someone else,’ Jennifer recalls. Other families at the conference suggested she contact Dr. Chiang, who at that time was at the University of Colorado in Denver.
“I emailed him that evening in our hotel room and he responded immediately, agreeing to help as much as he could,” she says. Within a week, Gavin’s blood samples were sent to Dr. Chiang, who analyzed his DNA for all genes known to be associated with LCA. When that search came up empty, he recommended whole-exome sequencing, which uses cutting-edge technology to analyze the entire protein-coding regions of the DNA, including known and unknown disease genes.
The family agreed to take this next step and Gavin’s blood work was sent on to BGI for whole-exome sequencing. After months of meticulous data analysis, Dr. Chiang and his team were able to narrow their search to NMNAT1, which previously had not been associated with blindness. Ten other patients subsequently were also found to have the gene variant, which was also found by three other research groups. Soon after attending this year’s LCA family conference this past summer, Dr. Chiang called Gavin’s parents to tell them their son’s gene defect had been verified.
“We had been waiting for the day to get this information,” says Jennifer, who has established a foundation in Gavin’s name to raise awareness for LCA and support research.
“I have no words to express my gratitude for Dr. Chiang, he’s absolutely amazing,” says Jennifer, describing her family’s experience during this effort.
“He never made us feel like a test tube. He’s always treated us as parents, going out of his way to clarify everything, give us updates and explain things,” she adds.
Now that Gavin’s gene has been isolated, the Stevens are hopeful that a cure will be available in his lifetime. “We want to raise awareness about Gavin’s condition to help other children as well. With this discovery, we hope other families will be getting that phone call. We know what that phone call meant to us.”
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NMNAT1 - Gene Discovery
I have been in the business of molecular diagnosis of rare genetic conditions for almost ten years. I have witnessed firsthand the tremendous progress in the last few years and I believe that I have contributed a fair share to the progress especially in the field of eye diseases. But the progress is clearly not enough to me because most affected families can still not benefit from it. Unfortunately, just like all the other medical advancements in this country, most of these new technologies are expensive.
The same kind of thinking and business model are prevailing again in our field even though most people would agree that medical cost in this country is unsustainable. It has become clear that the only meaningful way moving forward is to build an independent laboratory with its core interest on serving the needs of the community. In order to make the tests more affordable, cutting red tape and bureaucracy but not quality is essential.
Molecular Vision Laboratory (MVL) was founded by scientists and run by scientists. We focus on clinical utility including the cost of tests. Because even the best test can have poor utility if most people cannot afford it. We believe valuable resources should be spent on improving quality, increasing clinical utility and lowing cost. We aim to become a specialty laboratory for eye diseases and we hope to work with a broad group of clients domestically and internationally.
Message from Dr. Chiang
Contact Dr. Chiang
John (Pei-Wen) Chiang, PhD, FACMG
Molecular Vision Laboratory