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Rare Genomics Institute Secures Sequencing for Patients with Undiagnosed Diseases

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By Monica Heger

By partnering with
genomics research institutions and raising money through a crowdsourcing model, the Rare Genomics Institute is helping to ensure that patients who have undiagnosed diseases can have their exomes sequenced.

Jimmy Lin, the president and founder of the institute and a research instructor in the Genomics and Pathology Services division at Washington University's School of Medicine, told Clinical Sequencing News that the inspiration for the institute came about a year ago when he met a family with a child who had a rare disease.

"They had traveled to many institutions and no one could tell them what the disease was," he said, "but everyone was saying it was genetic."

That case started him thinking about the barriers for implementing clinical sequencing in cases where it made sense, and how those barriers could be overcome.

Three of the largest barriers, he said, are funding, a lack of connection between patients and researchers, and translating research back to patients and physicians.

RGI was set up to address these issues, and that first case is now set to undergo sequencing at Johns Hopkins next month, said Lin.

Lin said that before launching, he approached some of the leading clinical genomics researchers and asked whether they'd be able to provide sequencing services if he were to bring them a family whose child had an undiagnosed disease and if he also raised the necessary funds. "For the most part, it was a resounding yes," Lin said.

RGI now partners with 11 different research institutes in the US: the University of Washington, the Institute of Genomic Medicine at the Utah Foundation for Biomedical Research, the Barrow Neurological Institute in Phoenix, Washington University in St. Louis, Duke University, the National Cancer Institute, Johns Hopkins School of Medicine, Columbia University, Yale University, University of Maryland, and Harvard University.

Sequencing is done at the respective institutes, which sequence not only the patient but also both parents. Each trio costs between $2,500 and $7,500 and patients either pay out of pocket or the Rare Genomics Institute raises funds through a crowdsourcing model.

So far, Lin said, funds have been raised for two families and an additional two families have decided to pay out of pocket. A fifth is currently in the midst of fundraising, and there are around 30 patients total in the pipeline.

Similar to other crowdfunding sites like Kickstarter, which funds artists and other creative projects, RGI raises money through its website. Potential donors can use the site to see the families that are raising money, as well as the end goal and how much is needed to reach that goal, and then choose to support specific cases for any amount.

Lin said that so far the model has been successful — one family was able to raise the funds in one day and another within weeks.

The costs include not only sequencing, but analysis and interpretation as well. The institutions set the prices, Lin said, and costs vary because each institution receives different amounts of support and subsidy.

Patients are often referred to RGI by academic institutions or patient-advocacy nonprofits, said Lin. Upon referral, Lin has the patient's medical records sent to the institution that will do the sequencing. That institution reviews the case and determines whether it is a good candidate for sequencing. The family is linked with a genetic counselor.

Lin anticipates that one of the biggest hurdles going forward will be interpretation, since the patients have diseases that have not been identified previously. "Sequencing is just the start," he said.

Aside from the crowdfunding model, it is this interpretation step that will likely set the project apart from companies such as Ambry Genetics, which offers a clinical exome sequencing service for patients with rare diseases (CSN 10/5/2011), and GeneDx, which is also planning to launch a clinical exome sequencing test this month (CSN 10/12/2011).

"We're partnering with the leading experts for clinical interpretation," Lin said.

Patient Perspective

Jeneva Stone, whose son Robert will be RGI's first case, told Clinical Sequencing News that she heard about the institute from Syndromes Without a Name, a nonprofit organization that offers support and information to families of children with rare, undiagnosed diseases.

The family met with Lin, who "talked with us a lot about gene sequencing, what it could do, and what its limitations were," she said. Lin then connected the family with a geneticist at Johns Hopkins.

Robert is now 14 years old, and has already undergone a slew of tests to try to determine the molecular cause of his disorder, which affects his movement and speech. He is confined to a wheelchair and has to be fed through a tube.

Robert is "severely impacted" by his disorder, said Stone, adding that all of the molecular tests have been inconclusive so far.

In cases like Robert's, sequencing is thought to be a good option, and indeed, there have already been a number of examples where sequencing has pinpointed the molecular cause of an unknown disorder.

However, there are many issues associated with the use of sequencing in these cases, including questions around translating genomic data and providing clear interpretation to the patient. Additionally, some researchers have expressed concern about overselling the promise of the technology, noting that it cannot always find a diagnosis and, even if it does, that does not necessarily mean that there will be an effective treatment.

For Stone's part, she is aware that sequencing may not solve the mystery of her son's disorder. She is hopeful that it will, of course, but said that even if it does not, one goal would be that the sequencing would uncover "a catalog of unrecorded or unknown" mutations that could be kept with Robert's medical records, keeping the family "keyed into the research," she said.

"If someone down the line ends up doing research on those [specific genes or mutations], Robert could participate in the study. …That would be huge for us."

Additionally, sequencing raises concerns about privacy and what to do about incidental findings not related to the disorder.

Stone said she is less worried about privacy with regard to Robert's condition given that his condition is already known and so severe.

Because RGI's model includes also sequencing the exomes of Stone and her husband, she said that they are somewhat concerned about finding variants related to diseases for which they can do nothing about — such as cancer or Alzheimer's.

"Since my mother had Alzheimer's, that's a big question mark in my mind," she said. She added that she and her husband have discussed with their genetic counselor different possibilities on returning results, including not receiving data related to diseases like Alzheimer's.

Stone said that she and her husband have not yet made a final decision as to the types of data they would want to receive, although she said she is leaning toward having all medically relevant information returned, even if it indicates risk for a disease like Alzheimer's or cancer, because it could allow her to be part of research studies down the road.

How, or if, that information would have to be shared with the Stone's insurance provider is another question mark. Her insurance provider is not reimbursing the test, which helps reduce concern, but she said that if the sequencing did uncover variants indicating a disease risk, she would likely seek legal advice on "whether that constituted knowledge of an actual pre-existing condition."

These types of questions will need to be addressed in the near future, as sequencing is increasingly becoming used in the clinic.

Despite these issues, "the pursuit of some kind of diagnosis has outweighed any concern I had about privacy," Stone said.

Lin thinks that insurance companies will eventually reimburse for clinical exome sequencing, especially in these rare, difficult-to-diagnose cases, where exome sequencing will soon be less expensive than a host of single-gene tests.

When that happens, RGI will evolve to focus on a different aspect of clinical sequencing such as using the sequencing results to do a functional analysis of the variants or to create animal models for drug screens.

"Our vision is really personalized medicine," whether that means addressing the funding issues or the more downstream analysis and identifying drug compounds that target a patient's mutation, Lin said.


Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.