When Gene Tests Draw a Blank, Try, Try Again

December 1, 2017

Increasingly, a type of DNA analysis known as whole exome sequencing is being used to hunt for genetic mutations that may provide clues about a patient’s condition. If a mutation linked to the patient’s disease is found, that information is relayed to the physician to inform the diagnosis, and, in some cases, guide treatment. It seems so simple, until the gene test draws a blank.

“More often than not, the search for a genetic diagnosis turns up empty,” says David Goldstein, PhD, director of Columbia University’s Institute for Genomic Medicine. “But that doesn’t necessarily mean there is no genetic explanation. It could be that, at the present time, we just don’t know enough about the genes involved.”

In fact, new disease-causing genes and mutations are being discovered all the time. Such discoveries are reported in the medical literature and catalogued in a database that testing companies and researchers can access.

“When a patient’s DNA is first analyzed, we may be looking for something that hasn’t been discovered or catalogued yet,” says Erin Heinzen, PhD, assistant professor of pathology & cell biology and deputy director of the Institute for Genomic Medicine. “But what many people don’t realize is that after a patient’s DNA has been analyzed, it usually just sits in storage at the testing company instead of being reanalyzed.”

In a small study, conducted by the Epilepsy Genetics Initiative, a signature program of Citizens United for Research in Epilepsy (CURE), Drs. Heinzen and Goldstein show that reanalysis can pay off for children with epilepsy. The researchers reanalyzed the DNA of 54 children with a severe form of epilepsy called epileptic encephalopathy, which has a genetic cause in about 30 percent to 40 percent of cases.

Previous analyses of the children’s DNA, performed within the past five years, had come up empty, but upon reanalysis, the team found two individuals with novel variants of a disease-causing gene called SCN8A. The mutations were found in a region of the gene that was only recently recognized as clinically relevant.

Having a new genetic diagnosis opened up new treatment options. “For one of the patients, the physician had already suspected, before the reanalysis, that the patient’s epilepsy might be related to this gene and recommended phenytoin, a drug that can be more effective in some patients with SCN8A mutations,” says Dr. Heinzen. That patient had more than a 90 percent reduction in seizures after starting this treatment. The second patient, who has a milder disease, has not yet started the new regimen.

The reanalysis approach was pioneered by the Epilepsy Genetics Initiative (EGI), a program aimed at identifying genetic mutations in individuals with unexplained seizure disorders. EGI is the brainchild of Dr. Goldstein and epilepsy specialists Dan Lowenstein, MD, of the University of California San Francisco and Sam Berkovic, MD, of the Epilepsy Research Centre in Melbourne, Australia.

EGI compiles clinically generated exome sequence data from people with epilepsy, focusing on those without a genetic diagnosis. EGI reexamines the sequence data every six months, considering the latest available information.

“Although this was just a pilot study, our findings suggest that we might want to reanalyze sequencing data that was initially unproductive from patients with other disorders that are likely to have a genetic component, such as ALS, autism spectrum disorders, and a range of severe childhood illnesses,” says Dr. Heinzen. “Unlike other kinds of tests that provide the same results every time, we need to view genomic analysis as an ongoing opportunity, rather than a one-shot deal.”


The study is titled “De novo variants in the alternative exon 5 of SCN8A cause epilepsy encephalopathy.”

A complete list of EGI’s members, including their academic affiliations and conflicts of interest, is included in the paper. Additional support for the study was provided by the National Institute for Neurological Disorders and Stroke (U01-NS077303-04S1).