NEW YORK (GenomeWeb) – Quest Diagnostics and subsidiary Athena Diagnostics have replied to plaintiff Amy Williams, who is suing the firms for negligence that she says led to the death of her two-year-old son in January 2008.
It is now up to Margaret Seymour, a senior judge in US District Court in the District of South Carolina, whether Williams' case should be dismissed or decided by a jury.
Earlier this year, Williams sued Quest and Athena for negligence in classifying an SCN1A mutation in her son Christian as a variant of unknown significance in a 2007 report. Christian had a fatal seizure in 2008 after receiving increasing doses of sodium channel-blocking drugs, which are standard treatments for epileptic seizures. However, studies show these types of drugs worsen seizures in Dravet patients, and weren't helping Christian.
Williams alleges that if Athena hadn't misclassified the variant, her son wouldn't have died, since Christian's doctors would have been able to correctly diagnose the cause of his seizures and give him the right treatment. In her lawsuit, Williams points to two publications which identified the same mutation Christian had as having occurred in another patient suffering from epilepsy.
In their reply on Friday, the defendants in Williams v Quest/Athena continued to argue that Williams' lawsuit should be dismissed because the six-year time limit for bringing medical malpractice claims has expired since Athena issued a 2007 genetic testing report for her son. In that report, Athena identified a variant of unknown significance (VUS) in the SCN1A gene, but the defendants said that the test result would not have remained "inconclusive" had Williams and her son's father gotten tested.
SCN1A is a highly variable gene, and mutations are well known to cause an epileptic syndrome called Dravet, which occurs in one in 21,000 infants. Approximately 80 percent of Dravet patients have an SCN1A mutation, though not all SCN1A variations are pathogenic and may be benign. Some Dravet patients have mutations in other genes or no known genetic cause at all.
Doctors typically diagnose classic cases of Dravet based on clinical symptoms, for example when in the first months of life an infant starts having myoclonic seizures triggered by heat, fever, or after the first vaccination, and the seizures are resistant to treatment. But Dravet babies don't always present with typical symptoms and can have different kinds of seizures, and in those cases, the identification of a pathogenic SCN1A variant can lead to a definitive diagnosis.
According to Williams' lawsuit, in 2007, Christian's clinical geneticists were trying to pin down the cause of his seizures and had administered a battery of tests, among them an SCN1A genetic test from Athena. The lab identified a missense SCN1A mutation, but identified it as a VUS. But since the majority of missense mutations that cause Dravet arise de novo, the lab "strongly recommended" in the report that Christian's parents be tested to resolve the uncertainty about its pathogenicity.
Williams' lawyers have argued that because most missense SCN1A mutations are de novo, parental testing wouldn't have helped in classifying the variant, a reasoning that "completely misconstrues the significance" of such testing, according to Quest and Athena. "Testing of the decedent's parents in 2007 would have shown that decedent's variant was de novo … a critical fact that, if known at that time, would have supported a pathogenic classification associated with [Dravet]," they stated in their latest reply.
Williams has maintained, however, that neither the lab nor Christian's doctors informed her of the SCN1A test, and she didn't find out about it until years after his death, so she could not get timely testing. She claims she first saw Christian's 2007 SCN1A report in 2014, at which point the lab told her the variant had since been reclassified as pathogenic. Whether Williams had knowledge of the report in 2007 may be critical to her case, because South Carolina has the "discovery rule" for negligence cases, which would start the clock for bringing a claim much later and allow her to bring her lawsuit eight years after Christian's death.
As such, this is where Quest and Athena focused their arguments in their reply. The companies have asserted that they are a healthcare provider and that this case should be viewed as a medical malpractice case, instead of negligence. In South Carolina, plaintiffs entirely lose the right to sue a healthcare provider for medical malpractice after six years.
In her recent response to Quest and Athena's motion to dismiss the lawsuit, Williams submitted a new affidavit from pediatric neurologist Max Wiznitzer, who has stated that as a clinician, he should be able to rely on the results furnished by a high-complexity genetic testing lab when making a diagnosis. A VUS "classification provides little to no assistance with making a specific diagnosis," Wiznitzer stated.
But if his doctors had a right to rely on the test report in their diagnosis, Quest and Athena argue that the clock for bringing a claim should start from 2007 when Athena issued the report to Christian's clinical geneticist (the report names John Shoffner) and that should also suffice as notice to Williams. "Since the doctors' reliance on the 2007 report is the foundation of plaintiff's case, the constructive notice provided by the warnings in that report triggers the running of the time period to bring suit," they wrote. "Whether plaintiff did not actually see the 2007 report until 2014, therefore is entirely beside the point … What matters is that the decedent's doctors did, as the plaintiff herself alleges and relies on to show causation."
The defendants and plaintiffs have gone multiple rounds in their bid to convince the South Carolina federal district court to dismiss or take up the case. And while arguments on both sides have remained largely the same, the tone of Quest and Athena's reply this time is notably sharp and takes Williams to task for "flatly contradict[ing] her own pleading."
For example, they point out that Williams in one of her responses to defendants' motion to dismiss argued that the case should be viewed as a matter of negligence because Athena's alleged misclassification of a variant is "of a nonmedical, administrative, or ministerial type or result from a lack of routine care surrounding the publishing of test results."
In a footnote, Quest and Athena replied: "It is worth asking: If all plaintiff were alleging were a 'nonmedical, administrative, or ministerial' type of error, why did she feel it necessary to attach not one but two affidavits of medical doctors with her amended complaint, and another with her memorandum in opposition?" Williams' case has two supporting affidavits from Wiznitzer and one from Robert Cook-Deegan, who until recently was a research professor at Duke University's Sanford School of Public Policy and held an internal medicine appointment at the school of medicine. He is now a professor at Arizona State University's School for the Future of Innovation in Society.
Ultimately, Williams' case centers on her allegation that Athena, according to its own variant classification scheme in 2007, should not have deemed Christian's SCN1A mutation as a VUS in the first place, since the same variant had already been published in two papers as having occurred in an epileptic patient. Athena should have known this, Williams further alleges, since an author of one of the papers was Sat Dev Batish, who then was and still is Athena's chief director of genetics.
Christian's 2007 test report from Athena contained a glossary explaining how the lab classified a detected variant into one of seven categories: known disease-associated mutation, predicted disease-associated mutation, amino acid change of unknown significance, variant of unknown significance, inconclusive, indeterminate, or benign. According to this glossary, "known disease-associated mutations are documented in the literature to be associated with diseases inherited in a dominant manner."
Whether the information in published literature in 2007 was sufficient for establishing the pathogenicity of the mutation in question, what additional evidence since then led to Athena's reclassification of the mutation, and when that change was made, are all outstanding questions that will only be answered if Judge Seymour agrees to let a jury hear this case. If allowed to go forward, legal experts believe that Williams v Quest/Athena could define what constitutes the standard of care for a genetic testing lab.
Read GenomeWeb's ongoing coverage of this case here.