Christian Millare had a severe seizure on Jan. 5, 2008, and died. He was two years old. His mother Amy Williams is convinced, based on his medical records, the opinions of experts, and the published literature, that her son's life didn't have to come to such a premature end. Eight years later, Williams is suing Quest Diagnostics, one of the largest reference labs in the US, and its subsidiary Athena Diagnostics, which in 2007 tested Christian for mutations in the SCN1A gene.

In a lawsuit filed last month in the fifth judicial circuit court in Richland County, South Carolina, Williams alleges that because Athena failed to follow federal lab regulations and accurately classify the genetic mutation causing her son's epileptic seizures, he continued to receive treatment that worsened his condition and caused his death.

In 2007, Christian's doctors sent his blood sample to Athena to gauge if he had mutations in the SCN1A gene, which is involved in the mechanism that controls the flow of sodium ions from neuron to neuron. Defects in SCN1A can throw off this process, creating an imbalance of excitatory and inhibitory electrical impulses in the brain and causing seizures. Mutations in SCN1A are well known in the literature to cause Dravet syndrome, a severe form of epilepsy that impacts one in 21,000 infants. Dravet syndrome babies start having seizures a few months after birth and have developmental delays. The Dravet Syndrome Foundation estimates that 80 percent of patients will have an SCN1A mutation.

In the complaint, Williams accuses Athena of misclassifying her son's SCN1A mutation as a variant of unknown significance (VUS), meaning that the lab determined there wasn't sufficient evidence in 2007 to link the mutation to epilepsy or determine it was benign. Williams asserts there was enough evidence at the time that her son's mutation was disease-causing. The complaint cites two papers, one published in June 2006 and one published in March 2007, which mention Christian's specific mutation had been studied and seen in another patient who had epileptic encephalopathy. One of the authors of the 2007 paper, published in Brain, is Sat Dev Batish, who then was and still is Athena's chief director of genetics. Moreover, a patent that Australian firm Bionomics licensed to Athena for the development of its SCN1A test lists the mutation (1237T>A) that Christian had as one that "disrupts the functioning of an assembled ion channel so as to produce an epilepsy phenotype."

Further complicating matters, amid the litany of workups and tests performed on Christian, Williams claims the report that Athena issued in June 2007 with the VUS finding never made its way to her. She learned about it in 2014, while searching for more definitive answers to why Christian passed away. Newly married, Williams was fearfully considering whether she could have a child again. Uncertain if she had passed on a genetic abnormality to Christian, she didn't want to risk it. "My body can't go through it again," Williams told GenomeWeb. "My heart can't go through it." Williams was able to obtain the original VUS report from Athena in the fall of 2014, and learned that the company now had classified the SCN1A mutation as disease-causing. Athena issued an amended report in 2015, but the published studies listed in the document as evidence the lab used to make the variant classification are the same as the 2007 report.

According to the complaint, Athena's failure to provide additional information to support this variant reclassification is one of many violations of the Clinical Laboratory Improvement Amendments — the federal regulatory standards that all labs must follow when testing humans. CLIA requires that labs have adequate systems for delivering test results to physicians and tracking the entire analytical process. Moreover, the complaint also highlights sections of CLIA stating that labs must furnish additional information in a timely manner to ensure the test results are accurate. 

"Athena seemed to make a series of mistakes, according to the complaint. Although the initial mistake, while extremely unfortunate and ultimately tragic, may be chalked up to human error, it does appear that they did not follow their own variant classification scheme," said Girish Putcha, who has directed a number of clinical labs. He reviewed the plaintiff's complaint for this article but is not involved in the case.

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. In 2010, Athena launched a program called Athena Insight, which investigates the pathogenicity of variants and categorizes them on a seven-point scale.

"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 Putcha.

Further, "upon information and belief, prior to 2015, [Quest and Athena] recognized that a substantial number of patients were affected by similar erroneous SCN1A … sequencing reports," the complaint states. If the case goes forward, a jury will have to decide whether there was sufficient evidence in the literature in 2007 for Athena to determine a pathogenic link between Christian's mutation and Dravet.

When asked to provide comment for this article, Athena's parent company Quest declined to discuss pending litigation. Williams is suing the company for actual and punitive damages. She would also like to see some change in the law that holds labs more accountable.

John Conley, a law professor at the University of North Carolina, told GenomeWeb that if this case goes forward it could impact the standard of care provided by a genetic testing lab, but first, plaintiffs will have to prove that if Athena hadn't been negligent, Christian wouldn't have died. "That to me is their biggest challenge," said Conley, an expert in biotech and IP law. "The link between a genetic test and an outcome is so complex and attenuated, that's going to be hard to explain factually and hard to prove."

Right now, there are no mandated standards for how labs classify and interpret detected variants, and report genetic test results. The American College of Medical Genetics and Genomics published updated guidelines in this regard in 2008 and again in 2015, and while accrediting bodies say labs should adopt these standards, it is voluntary. There's no requirement that labs be transparent about their variant classification process and report data from genetic test results into publicly accessible databases. And although recent laws now allow patients access to their lab results, in the field of genetics, where variant interpretation and reporting standards are still evolving, there is little agreement among industry players, regulators, and medical professionals about what information to return to patients, how to present this information in reports, and whether it should go directly to them or through a doctor, particularly when VUS are involved.

Robert Cook-Deegan, an expert in genomic testing policy and ethics at Duke University, said this case "exposes an incredible flaw" in the genetic testing field right now, in the way labs interpret whether a particular genetic variant is associated with disease and how that information gets published, finds its way into public databases for others in the field to evaluate, and makes its way into providers' and patients' hands. "As far as I know, [Christian's] case has never been reported in the literature," said Deegan, who filed an affidavit on behalf of the plaintiff stating his opinion that Athena breached the standards of care for a high-complexity genetic testing laboratory. "A kid dies from a misdiagnosis, and the system doesn't even notice that because it doesn't get incorporated into the data structures any place."