Christian Millare had his first seizure when he was 4 months old. His mother, who’d never seen a seizure before, thought he was shivering from cold. From then on, every virus or fever would cause another seizure. Eventually his brain had suffered enough damage and he died after a seizure at age 2.
Christian’s mom Amy Williams had pursued every avenue to find out the cause of his repeated and worsening seizures. That included genetic testing. When he was sequenced for rare disease mutations that cause seizures, Athena Diagnostics found a ‘variant of unknown significance’ in a gene known to be linked to such a disease, Dravet syndrome. But because the lab didn’t specifically identify the mutation, Christian was kept on a line of seizure treatment that may have killed him.
Now his mother is suing Athena and its parent company Quest for negligence. The evidence that the laboratory knew of the significance of Christian’s mutation and should have informed Williams is damning but not only to the defense. Christian’s case shows that the current regulatory landscape for genetic tests is failing far too many patients.
Seizures in children are fairly common. Epilepsy is on of the most common neurological conditions in the U.S. There are lots of treatment options including medications and diet. But there are also underlying medical conditions that can cause repeated seizures. Mitochondrial diseases are an extremely rare subset of those conditions. Williams and the physicians caring for her son suspected that a mitochondrial disease might be responsible in Christian’s case. But the genetic testing needed to identify the mutation was not completed before his death.* Instead, the neurologists treating him adopted what they thought was the best treatment, continuing him on medications, the DNA Exchange explains:
Apparently, the physician who ordered the test decided that the genetic test result was inadequate to help establish a definitive diagnosis, and pursued other diagnostic possibilities. As far as can be gleaned from the records, the genetic test results were not shared with the family although some of the treating physicians had considered the diagnosis on clinical grounds. The child continued to be treated with medications that, unfortunately, worsen the seizures for the condition that the child was ultimately diagnosed with – a condition caused by mutations in the gene in which the VUS [variant of unknown significance] was found.
We now know that the genetic tests ultimately revealed the cause of Christian’s condition. There was an identified mutation in the gene, but the geneticists and physicians didn’t know exactly what it was. Unfortunately, that wasn’t communicated to Williams or the doctors treating her son. And, although it is the protocol, the laboratory didn’t update the result when the variant’s significance was made known just a few months later. In fact, the head of the gene testing lab was an author of the study that definitively linked Christian’s mutation to Dravet syndrome. The mutation in this condition misshapes the pores on the surface of neurons that control the release and influx of sodium into and out of the brains cells.
Christian’s seizures would have continued even with a correct diagnosis. But his mother thinks if the genetic testing company had correctly identified the mutation he might still be alive. While data is poor on life expectancy with the condition, it is possible for sufferers of Dravet syndrome to live into adulthood — albeit with severe disabilities both mental and physical. The course of the condition varies for most people, but many experience a lessening symptoms when treated with anti-convulsants and a diet high in fats and low in carbohydrates. Unfortunately Christian’s case points to a lack of accountability, standardized practices and oversight of medical genetics.
The Center for Medicare and Medicaid oversees all laboratory testing, including genetic tests, via the Clinical Laboratory Improvement Amendments (CLIA). The CLIA laws mandates a system for tracking diagnoses and updating test results as more information becomes available. But there is limited oversight beyond the law and each lab is responsible for classifying and updating variants as research dictates, and then informing patients and physicians of those changes. Athena failed its job, Turna Ray reports at GenomeWeb:
The complaint notes that, based on Athena’s own variant classification criteria described in the 2007 report, Christian’s mutation should have been deemed an “amino acid change of unknown significance,” instead of a VUS. “The subsequent failure to notify the patient and his caregivers in a timely manner when the error was noticed and a change [was] made to the final test report, followed by what appears to be a deliberate attempt to delay such notification and/or conceal the mistake altogether, not just for this patient but perhaps for others as well, is especially disturbing,” said Girish Putcha [who has directed a number of clinical labs].
CLIA must be updated so that there are standardized processes to classify gene variants and update patients. The federal government already funds a database of disease-causing variants, ClinVar under the National Institutes of Health. Another resource, ClinGen, is a private database of variants aimed at improving patient care by putting all this information in one place. Patients can even upload and share their own anonymized data. PROMT is another patient-focused initiative that lets people with cancer who have had genetic analysis input their data in hopes of advancing public health research.
These programs are worthy of the research dollars and support they get. But a patient can’t be expected to discover all of this on his or her own. Our health care system has got to get on top of the genetics revolution and accept the complexities it presents when treating patients. And legislation that protects patients needs to be updated to deal with the new, ever evolving types of information that genetics provides.
Even patients who seek out genetic counselors cannot totally be sure they are getting the correct information. An investigation by Beth Daley at the New England Center for Investigative Reporting showed that counselors are being recruited and payed by genetics testing companies rather than the doctors offices they work in. Most states don’t even have a licensure process for counselors, which the National Society for Genetic Counselors is working to remedy.
The most troubling part of Williams’ lawsuit is that it alleges that this mistake went beyond Christian. Her court complaint says that a ‘substantial number’ of other patients also received erroneous reports of mutations in the same gene. Let’s hope they had the time, money and presence of mind to get a second opinion.
Meredith Knight is a contributor to the human genetics section for Genetic Literacy Project and a freelance science and health writer in Austin, Texas. Follow her @meremereknight.
3/28/16: This article was changed to reflect that Christian’s genetic tests for mitochondrial disease weren’t completed before his death. His autopsy later indicated it might have been the cause of his condition. We also corrected the title of GenomeWeb. Thanks.