Efforts Expand Whole-Genome Sequencing for Rare Diseases

Multiple efforts are expanding the focus of sequencing, particularly whole-genome sequencing (WGS), for improving diagnosis of rare diseases. Likened to finding the proverbial needle in a haystack, identification of a single, rare, disease-causing mutation can bring families some semblance of closure—a genetic cause for the condition, if not a treatment option.

Families and medical experts are hopeful that a spate of recent announcements expanding access to sequencing-based evaluations for rare and undiagnosed diseases can bring an end to years of unfulfilled diagnostic odysseys. In the United States, it has been estimated that 30 million people suffer from a rare disorder.

Seven additional clinical sites (Baylor College of Medicine, Duke Medical Center, Columbia University, Harvard teaching hospitals, Stanford Medical Center, University of California at Los Angeles Medical Center, and Vanderbilt University) have been added to the original Undiagnosed Diseases Program (UDP) at the National Institutes of Health's Clinical Center in Bethesda, Md. in mid-September. The NIH plans on using $145 million in Common Fund support over the next seven years for the expanded Undiagnosed Diseases Network (UDN). All applications for evaluation within the network will go through an online patient application portal, rather than through each individual clinical site. Sequencing will be performed at two core sequencing facilities—Baylor and HudsonAlpha Institute for Biotechnology (in partnership with Illumina).

The original UDP has enrolled more than 800 undiagnosed patients for one-week evaluation since its launch in 2008. Over the seven years, 25 percent of those have received some level of clinical, molecular or biochemical diagnosis, the NIH says. Of 160 patients who were admitted during the first two years of the service, diagnoses were made in 39 patients. Diagnoses included two previously un-described disorders, 23 rare or ultra-rare diseases in 28 patients, and nine common conditions, including fibromyalgia and multiple myeloma. The UDP estimates that approximately half of its diagnoses were made directly from agnostic genetic testing, such as whole exome sequencing (WES). The remaining diagnoses were made using targeted biochemical, radiologic, and molecular studies advised by rare disease specialists.

The hope is that with the additional clinical sites, more patients will be seen (50 per year per site by summer 2017) and sharing of variant information among the network sites will up the diagnostic yield. The principal investigators of the expanded network are looking to WGS and WES to provide "better answers" to these families who often go on decades-long, "diagnostic limbo."

"Although undiagnosed conditions present an array of challenges for clinicians, once identified, they may ... lead to new, generalizable medical insights," said James Anderson, M.D., Ph.D., from the NIH, in a statement.

HudsonAlpha, one of the core UDN sequencing sites, says it will sequence at least 1,600 genomes over the next three years while Baylor will sequence an equivalent number of exomes. The diagnostic yield of the two methods will be compared. HudsonAlpha says it hypothesizes that WGS will increase the diagnostic success rate 25 percent more than WES.

Efforts to improve diagnosis of rare diseases are occurring abroad as well. Chinese firm WuXi AppTec, which provides next-generation sequencing solutions to academics, the life science industry, and medical institutions, announced in September that WuXi NextCODE and its WuXi Genome Center, China's only CLIA-certified clinical genomics lab, will provide sequence-based testing for cases of unresolved diagnosis at Children's Hospital of Fudan University (CHFU). CHFU sees 2.3 million patients annually.

"Using the emerging global standard for genomic data in medicine, we can move beyond static gene panels to employ the full power of the genome to address rare diseases, genetic and genetics-related disorders," said CHFU's President Guoying Huang in a statement.

Takeaway: Beyond the potential for genetic discovery, use of WES and WGS sequencing through expanded collaborative efforts is raising the hope of improved diagnostic yield for rare, undiagnosed diseases.