At a time when many in the genomics community were betting that whole-genome sequencing would be the path forward in the clinic, Madhuri Hegde made a strategic decision to focus on gene panel testing instead. Today, just a few years later, countless clinical geneticists are following in her footsteps.
That’s no surprise, given her leadership position in the community. Hegde, a board-certified molecular geneticist, serves as Executive Director of EGL Genetics, which she joined in 2006. The Emory lab, founded nearly 30 years ago and serving physicians around the world, has a staff of more than 100 across its biochemical, cytogenetic, and molecular testing labs. Hegde is also on the board of directors for the Association for Molecular Pathology, and serves as a member of the American College of Medical Genetics and Genomics’ next-generation sequencing guidelines committee and a representative to the CAP molecular resource and next-generation sequencing committees.
Her colleagues and other genetic testing lab directors are increasingly seeing the value of gene panel tests, which sequence a pre-selected set of genes known to be associated with a disease of interest. A patient who comes in with an unknown form of neuromuscular disorder, for instance, might have his diagnosis pinpointed by a panel test, which sequences variations across 70 genes previously linked to neuromuscular disorders. On the other hand, an exome or whole-genome sequence — which does not completely cover the exome — would yield results across thousands of genes that might have nothing to do with the patient’s clinical presentation, generating a confusing list of unknown or irrelevant variants to be reported to a physician. “If you look at panels, they really offer the opportunity to completely interrogate the mutation spectrum of a gene or genes known to be associated with the disorder — all the point mutations, deletions, duplications. We have seen a five-fold increase in mutation detection rate for neuromuscular disorders,” says Hegde, who runs these gene panel tests using the RainDance Technologies targeted sequencing platform. “And when new genes are identified for that disorder, we can easily add genes to panels.”
To be sure, Hegde’s lab also performs exome sequencing as well as single-gene sequencing. But she says that those are best used in very specific cases: exome when the physician is not able to have a clear clinical diagnosis, and single-gene in most cases when the physician already has a diagnosis and is looking to confirm the mutation. For the majority of patients — those whose phenotype suggests a possible diagnosis but does not point to one specific gene — “I think the panel test is the right way to start,” Hegde says. Her lab currently offers 10 gene panel tests, each focused on a particular disease or disorder, that provide the physician comprehensive results within that specific disease focus. Targeted panels also have the benefit of a shorter turnaround time than assays covering more of the genome, Hegde says.
The Emory panels include autism spectrum disorders, cardiomyopathy, ciliopathies, epilepsy, eye disorders, neuromuscular disorders, short stature, and X-linked intellectual disability, among others. Each panel tests anywhere from 10 to 140 genes, and panels can be subdivided further in cases where physicians have a more specific region to assay. The Emory lab uses both the RDT 1000 instrument and the higher-throughput ThunderStorm™ targeted sequencing instrument from RainDance.
Like other genomic technologies, gene panel tests are very new to clinical labs. In her remit as director of a CLIA- and CAP-certified genetic testing laboratory, Hegde is responsible for getting to know all new molecular testing technologies. The CLIA approval and classification as a high-complexity lab means that Hegde and her team may bring in the most cutting-edge technologies and use them for patient samples so long as they perform validation and quality control protocols. “We have been focusing on bringing in cutting-edge technology to offer high-quality genetic testing,” she says. “We are able to bring in new methods and develop all these new techniques.
In that spirit, Emory was “the first clinical lab to get into next- gen sequencing,” Hegde says. Being early clinical adopters of sequencing meant figuring out what to test and how to report that back to physicians, who had little interest in seeing all 3 billion bases of each patient’s DNA. In 2010, Hegde’s team brought three new target capture technologies into the facility and evaluated them for their ability to reliably and reproducibly select predefined sections of the genome that could then be run on a next-gen sequencer. After a rigorous comparison process, Hegde chose the RainDance platform for its uniformity of coverage, reliable results, automation, and ease of use; she then followed CLIA rules regarding use of the platform in her lab. The ease of use was particularly important to Hegde, who factors in all costs — including hands-on time — when considering the operating cost of a new instrument. “The ease of operation, ease of designing the libraries, and ease of using the instrument in the lab made a huge difference,” she says. Other platforms required hours more time from technicians, adding in a cost that wasn’t obvious in the upfront price of instrumentation. Hegde says that for a clinical lab, any tool that can reduce the amount of Sanger needed or reduce the hands-on time for technicians “makes a lot of sense.”