Did you know that of the nearly 20,000 genes that humans possess, only a quarter are currently known to cause genetic disorders? The remainder often referred to as “novel or candidate disease genes” are yet to be connected to a genetic condition, and many patients can remain undiagnosed until new disease gene discoveries are made. Less than a decade ago, these discoveries were chugging along at a snail’s pace until they suddenly hit warp-speed with the development of new technologies, which allowed us to sequence all of a person’s genes in a single test at a fraction of the cost and time taken by previous methods!

We are driven to give healthcare providers the most advanced testing information available so they can determine the best treatment options for their patients. Ambry has been the first to adopt the latest and greatest of these technologies, including whole exome sequencing, long before any other clinical laboratory recognized their potential to improve diagnosis. Since launching clinical exome sequencing in 2011, Ambry has helped discover more than 150 new candidate disease genes (Farwell-Hagman, 2017).

In this video, Dr. Nunes talks about one such novel disease gene discovery made by Ambry that finally provided the answer for his patient, Kavish, a 10-month-old boy who had infantile-onset epileptic seizures. Multiple genetic tests had failed to find a diagnosis for Kavish until Dr. Nunes sent his sample to Ambry in 2014 for exome testing. Because this technology scans all genes, and not just those that have been previously linked to a genetic disorder, Ambry’s scientists were able to identify a sequence change in the novel candidate disease gene for dynamin (called DNM1) using a rigorously validated set of analytical criteria. At the time, DNM1 was known to be very important for the normal function of the brain, but was still a novel disease gene in humans, although mutations in this gene were known to cause epileptic seizures in mice. Dr. Nunes and Kavish’s parents were excited to get this result, but faced many questions: what did it mean, and what’s next? Were there more patients out there with mutations in this gene, with the same type of epilepsy as Kavish? And more importantly, were there any anti-epileptic treatments that could benefit Kavish?

Fortunately for them, within a couple of weeks, a new scientific study confirming DNM1 as a human epilepsy gene was published by an international group of physicians and researchers from Europe who specialize in the discovery of new epilepsy genes and treatments (EuroEPINOMICS/Epi4K Consortium, 2014). This helped fit the final piece of the puzzle in Kavish’s diagnosis, and also gave him, his family and Dr. Nunes the opportunity to connect with the European group and other patients with DNM1 mutations for further research. Since then, more than 20 epilepsy patients with mutations in the DNM1 gene have been identified (von Spiczak, 2017). Efforts are on-going to understand how it causes epilepsy and discover treatments which could improve the quality of life for these patients and their families.

So why does Ambry invest all this time and effort in analyzing novel disease genes? Because identifying and reporting changes in novel disease genes to patients and their physicians is the key first step in the discovery of new disease genes. Not only does it help with early medical treatment for the patient, but also paves the way for scientists around the world to identify more patients and confirm that specific gene as a well-known disease gene for the diagnosis of future patients. And it fits with Ambry’s mission: “Putting patients and understanding of genetics above all else.”

Farwell Hagman KD, et al. (2017) Candidate-gene criteria for clinical reporting: diagnostic exome sequencing identifies altered candidate genes among 8% of patients with undiagnosed diseases. Genet Med, 19(2): 224-235

EuroEPINOMICS-RES Consortium; Epilepsy Phenome/Genome Project; Epi4K Consortium (2014) De novo mutations in synaptic transmission genes including DNM1 cause epileptic encephalopathies. Am J Hum Genet, 95(4): 360-370

von Spiczak S, et al. (2017) DNM1 encephalopathy: A new disease of vesicle fission. Neurology, 89(4): 385-394