A focused genetic testing approach ends a 32-year diagnostic journey
Jackie Smith, a 35-year-old mother of two, searched for 32 years for the cause of her muscular weakness. Claritas helped find the answer in 3 weeks. Jackie’s parents knew something was wrong soon after she was born. At first, because her ankles turned in, they thought she was bow-legged. At three, Jackie underwent a muscle biopsy and was diagnosed with centronuclear myopathy—so named because the nucleus of the muscle cells, instead of being located at the edges of the cells, is in the center.
Jackie’s family was told that she would likely die in childhood, but that if she survived, her condition would not progress. Neither was true. Jackie learned to walk, but grew weaker in her teens and now uses a wheelchair. Like many people with muscular disorders, she eventually gave up on finding a diagnosis, seeking medical care only for her symptoms.
Because gene discovery for muscle conditions is a recent development, many health care providers still do not recommend gene testing for patients with these rare disorders. “The typical advice to parents is that a genetic diagnosis doesn’t matter if there is no current treatment or cure,” says Anne Rutkowski, MD, director of CMDIR, the Congenital Muscle Disease International Registry.
Jackie learned of CMDIR, a comprehensive database of people with a variety of congenital muscle diseases, through an online search. She reached out, and in early 2015, Rutkowski suggested she try genetic testing one more time. She had heard that Claritas Genomics was taking a new approach and had a test in development that could provide rapid results.
From sequencing to drug screening
This new test, called the Pediatric Neurology Region of Interest, was developed in collaboration with experts from Boston Children’s Hospital and uses an innovative next-generation sequencing approach in which two separate and independent processing methods simultaneously capture and sequence hundreds of genes related to neurological disease. The rapid test was made possible through Claritas’ framework, which brings together disease experts, sophisticated technologies and gene databases.
Jackie became the first person to be tested using the Pediatric Neurology Region of Interest. Her results arrived merely three weeks later: her centronuclear myopathy was caused by two rare variations in the same gene, RYR1. RYR1 encodes a protein called the ryanodine receptor, found only in muscles. The protein forms a small pore or channel that allows calcium to flow out—an essential step for muscles to contract.
“In resting muscle cells, calcium is stored in a balloon-like structure called the sarcoplasmic reticulum,” explains Alan Beggs, PhD, head of the Manton Center for Orphan Disease Research and an expert in congenital muscle weakness. “When a nerve impulse reaches the muscle, the ryanodine receptor channels open up and calcium floods into the body of the muscle cell to trigger contraction.”
How exactly RYR1 mutations interfere with this process isn’t clear. In some cases, the defective channels are leaky so that the calcium flows out before enough builds up to initiate a muscle contraction. Other mutations prevent the channels from opening properly. In any case, Beggs and his team are looking for potential drugs to reverse the damage—with help from zebrafish.
In zebrafish, the mutations cause muscle weakness just as it has in Jackie. The researchers can use them to screen potential drugs by simply adding compounds to the fishes’ water and seeing if any improve their ability to swim. Beggs’s team has already found a few promising candidates, and if any of those drugs are successfully developed, Jackie and others like her with RYR1 mutations would be candidates for treatment.
What a difference a gene makes
There is no treatment yet for centronuclear myopathy, a disappointment for Jackie and her family, but knowing that a gene called RYR1 is the cause of her condition has made a world of difference.
“For me, it has been about information,” she says. “I found out how it could affect my children. I now know that my girls are carriers and all of us can plan for the future better. It’s important for me that they can make informed choices. They’ve seen what I’ve gone through and that will help them with their family planning.”
Jackie has begun corresponding with other people with similar RYR1 variations. This has given her a community she did not have before—people who know exactly what she is going through.
Through its close association with Boston Children’s, Claritas is able to connect patients who want to contribute to rare disease discoveries with research opportunities. Beggs has been collecting genetic data from congenital myopathy patients and their families since the early 1990s, and Jackie recently enrolled in one of his studies.
“Claritas’ Pediatric Neurology Region of Interest has allowed us to leapfrog past the genetic testing stage to identify mutations that we can study further to develop treatments,” says Beggs, also a professor of pediatrics at Harvard Medical School. “Without this test, it might have taken us a year or longer to identify the changes in Jackie’s RYR1 gene. The ability to do so in three weeks frees up more time to study her muscle and how similar mutations affect zebrafish or mice, so that we can use those model systems to develop new treatments.”
An added benefit, Beggs says, is that Claritas’ laboratory is CLIA-certified and the Neurology Region of Interest is a clinical test, so results can be used to help treat patients. Jackie’s story illustrates the Claritas mission: To expand the rate of diagnosis, improving tests and technology use, and by making information and expertise available to healthcare providers around the world.