Aware for Rare: Exploring Current Challenges in Rare Disease - PART II


In this four-part series, we examine the various challenges faced by patients and families affected by rare diseases. We also interview clinicians, researchers, and the advocacy community at large to understand their perspectives on bottlenecks in rare disease diagnosis and treatment.

Part 2 of the series discusses options if Next Generation Sequencing does not provide a diagnosis as well as the lack of effective treatments and therapies to cure rare diseases.

Next Generation Sequencing Doesn’t Always Give the Answer

When patients are able to secure Next Generation Sequencing (NGS), they begin a process that typically takes 4 to 6 months to complete. For a genome sequence, about 3 to 4 million variants must be interpreted. At the end of the day, some patients receive a diagnosis, but many are still left without one.

“Separating the hype from reality can be challenging,” said Leslie Biesecker, chief of the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute (NHGRI) of the National Institutes of Health. “Genomic testing, like every other medical test is neither 100% predictive nor 100% sensitive. It never will be and should never be expected to do so. However, it can still be incredibly powerful and useful.”

According to Cincinnati Children’s Hospital clinical geneticist Loren Peña, the current diagnostic yield for whole exome sequencing (WES) ranges anywhere from 25 to 40 percent, which means that it is possible for 60 to 75 percent of patients to be left with no diagnosis after WES.

“That’s a significant number,” Peña said. “We have learned that the diagnostic yield for exome sequencing results is not as high as we had imagined, and it is clear that we need to think of other ways to either sequence or to analyze the raw data in order to improve the diagnostic yield.”

Often, the alternative approaches include re-analyzing existing raw sequencing data or referring patients for research protocols. For patients who remain undiagnosed even after WES or WGS, Peña stresses the importance of scheduling yearly follow-ups to establish an iterative process of re-analysis and reconsideration of additional testing, including examining exomes with new genome builds, integrating information about new diseased genes, or re-evaluating negative results.

“There is some emerging data suggesting that anywhere from 10 to 15 percent of patients who have already undergone WES and who undergo reevaluation, such as looking at candidate variants of uncertain significance and finding out if those can be reclassified, can end up receiving a diagnosis,” Peña said.

Through re-analysis, the Rare Genomics Patient Research Services (RGPRS) program has been successful in helping to identify potential disease causing variants in the WES and WGS data of undiagnosed patients. According to Rare Genomics (RG) Chief Scientific Officer Imran Babar, the goal of RGPRS is to bring patients one step closer to actionable information that can ultimately benefit their health at no cost.

“While obtaining sequencing data is an important step, it's the accurate analysis of these data that is particularly helpful for patients,” Babar said. “RGPRS was formed to provide rare disease patients with access to scientifically trained experts who employ cutting-edge analysis tools to help unravel complex information contained in sequencing data.”

Babar notes that while other institutions and programs also offer sequencing re-analysis, and at higher volumes, the RGPRS process is highly personalized and has been successful in identifying functionally significant variants that have been missed by others.

“RGPRS focuses on the individual N=1 model, where each patient project is highly valued and prioritized,” Babar said. “The initiative aims to fill the gap for patients who may not otherwise have access to the highest quality sequencing analysis tools and services.”

Patient derived genomic data analysis is a complex process and requires specialized software tools and expertise. Analysis of data includes sequence alignment to a reference genome, variant calling, variant filtering, as well as ranking and prioritization based on pathogenicity. Interpretation of these results and surveying the published literature accurately and comprehensively in context of variants in question is also critical in decision making. Scientists at RGPRS rely on leading technologies for re-analysis of genomic data. RG has built a successful partnership ecosystem with technology providers including Variantyx and Genomenon, where access to software is provided pro-bono by partners so that patients can benefit.

"RG’s work on improving patient diagnosis through re-analysis (with the RGPRS program) is phenomenal, and is making a real difference in people's lives,” CEO of Genomenon Mike Klein said. We are proud to partner with them in diagnosing rare diseases by providing access to the Mastermind Genomic Search Engine to comprehensively search the medical literature. Mastermind assures that no genomic research relevant to the patient’s DNA is missed in their re-analysis process.”

What about a Cure? Finding Effective Treatments and Therapies

Still, for patients who are able to overcome the diagnostic barriers and who receive a diagnosis early on, a cure is not always in sight and potential treatments or therapies may be limited.

“After we figure out what the diseases are and how they work, the next question is whether we can actually do anything about that--whether we can develop treatments and how we then take those treatments to the bedside to help patients,” geneticists at Washington University in St. Louis said.

Yet as it stands, over 90% of rare diseases do not have an FDA approved treatment or therapy, according to Charlene York, who is serving her second year as the Ohio State Ambassador for NORD’s Rare Action Network. Further, much like obtaining NGS, treatments and therapies for rare diseases can be expensive.

“Ohio [in particular] has room for improvement in several areas including medical nutrition, out of pocket protections, individual insurance protections, and step therapy,” York said.

However, with substantial discoveries in all facets of genomics, from technology development, to basic science research, to clinical trials, progress is being made toward developing treatments for patients with rare diseases.

According to Biesecker, research will need to continue to encompass a broad portfolio of genomic science because “today’s basic science is tomorrow’s new diagnostic or treatment advance,” and it is the synthesis of new information from what is currently known about the genome that informs the next research steps.

As for the Nelsons, Joanne realizes that no treatments can reverse the damage that has been done to Luke. However, she remains comforted by the knowledge she has obtained with a diagnosis for her sons.

“We know what things this syndrome attacks, and we can be proactive in everything--getting plans and the right specialists involved--and help make our boys’ lives the best and happiest that they can be,” Joanne said. “While [Arts Syndrome] is a devastating, gloomy diagnosis with no cure, there is a treatment that has been shown to help with symptoms. If we can get [Clay] on treatment right away, his quality of life could be vastly improved and his deterioration slowed...who knows what kind of impact this early knowledge could have on his life?”

Watch this space for Part III of the series, which details some of the other challenges in the rare disease space: continued confusion and not knowing even after a diagnosis, scattered rare disease communities, and getting the attention of governments to intervene.