Williams v. Quest Diagnostics, Inc.

Christian Millare was born in August 2005 and beginning at the age of 4 months started having seizures. His doctors treated his seizures with sodium channel inhibitor medications: oxcarbazepine (Trileptal®), carbamazepine (Tegretol®), and lamotrigine (Lamictal®). These are standard treatments for epileptic seizures not caused by Dravet syndrome (SMEI). In January 2007, Christian’s DNA was sent to Athena Diagnostics (a subsidiary of Quest starting in 2011) for a DNA analysis of the SCN1A gene—that is, the detection and diagnosis of any DNA variants within the SCN1A gene. DNA mutations in SCN1A are associated with a spectrum of epilepsy phenotypes, the most severe being Dravet syndrome. For patients with SCN1A mutations, sodium channel inhibitor medications are to be avoided because they exacerbate the seizures. The DNA sequencing of Christian’s DNA took place in May 2007. The results were sent to the ordering physician, John Shoffner, on June 30, 2007. This report indicated that Christian possessed a DNA variant in the SCN1A gene that was classified as a “variant of unknown significance” or VUS (i.e., not specifically known to be either pathogenic or benign). Relying on the information in this report (which did not identify any DNA variants as being pathogenic or warn of any treatments to avoid), Christian’s doctors continued to treat him with increasing doses of multiple sodium channel inhibitor medications. Athena did not issue a copy of the June 2007 report directly to the patient or the patient’s family. Christian’s condition worsened, even as doses of the sodium channel inhibitor medications were increased in attempts to manage his seizures. Christian suffered a severe and ultimately fatal seizure resulting in his death on January 5, 2008.

His mother, Amy Williams, sued Athena and Quest, its parent company, in a South Carolina state court in March 2016. The defendants were able to “remove” the case to the South Carolina federal court because the plaintiff and defendants are citizens of different states. Nonetheless, South Carolina state law will continue to apply.

The complaint alleges that Athena was negligent and breached the applicable standard of care by (1) failing to provide a genetic confirmation that Christian had Dravet syndrome and (2) failing to adhere to its own DNA variant classification criteria. The alleged negligent misclassification of Christian’s DNA variant originates from the fact that in 2007, Christian’s DNA variant had been reported, studied, and known in a patient with Dravet syndrome. Specifically, a genotype-phenotype association between his variant and Dravet syndrome had been established in two clinical publications, Berkovic et al., 2006, and Harkin et al., 2007. Per Athena’s DNA variant classification criteria as defined in the June 2007 report, the requirement for deeming a variant to be a “known disease-associated mutation” was whether it was reported in the literature to be associated with the disease. Thus, the plaintiff alleges, the existence of Berkovic et al., 2006 and Harkin et al., 2007 made Athena’s classification of Christian’s variant as VUS (i.e., “has not been correlated with clinical presentation and/or pathology in the current literature”) demonstrably false. According to the June 2007 report, “the results of this analysis cannot be definitively interpreted due to the absence of published studies correlating these variant(s) with clinical presentation and/or pathology.”

Christian’s June 2007 report was signed off by Sat Dev Batish, chief director of genetics at Athena, and also an author of the Harkin et al., 2007 publication. According to the complaint, Christian’s DNA variant was cited as an SCN1A DNA mutation that “disrupts the functioning of an assembled ion channel so as to produce an epilepsy phenotype” in a patent for SCN1A testing. This patent originated from the laboratory that produced the Berkovic et al., 2006 and Harkin et al., 2007 publications—the same laboratory that also licensed use of the patent for SCN1A testing to Athena in 2004. Thus, the information used to gain patent rights of SCN1A testing included a citation of Christian’s variant causing an epilepsy phenotype. Finally, the June 2007 report lists a manuscript that was published in 2005 as “pending,” suggesting that Athena’s integration of the biomedical literature into their DNA variant database was at least two years behind…

At the hearing, Williams’s lawyer argued that these are acts of ordinary negligence, with a three-year statute of limitations that didn’t start to run until she discovered the negligence. Williams claims she was unaware of the June 2007 report until September 2014, at which time the June 2007 report was requested and received from Athena. During this 2014 interaction with Quest/Athena, Williams learned that the variant had now been deemed disease-causing and the report would be revised. Quest/Athena subsequently issued a revised report with the new classification of “known disease-associated mutation” on January 30, 2015. Williams contends that she had no opportunity to discover the defendants’ error until she had both the June 2007 and January 2015 reports in hand. Quest/Athena argued that it doesn’t matter whether or not the plaintiff herself knew or did not know about the 2007 report, because “the actual knowledge is imputed to the principal by virtue of [her] agent’s notice”—the agent in this case being the physician, John Shoffner, who ordered the test and received the June 2007 report. Williams also contends that Athena’s failure to notify anyone of the reclassification of Christian’s DNA variant prior to January 30, 2015 was a daily, recurring failure to comply with CLIA regulations, and thus represents a continuous and ongoing injury, each instance allowing for a new claim and thus starting a new clock…

According to the complaint, Williams believes that because a genotype-phenotype association between Christian’s DNA variant and Dravet syndrome had been established in two clinical publications (Berkovic et al., 2006 and Harkin et al., 2007), the June 2007 report should have classified Christian’s mutation as a “known disease-associated mutation” rather than a VUS. The existence of these two clinical publications would apparently satisfy the requirements of a “known disease-associated mutation” per Athena’s own DNA variant classification criteria as defined in the June 2007 report. (The requirement for deeming a variant to be disease-causing was whether it was reported in the literature to be associated with the disease.) Williams further alleges that classifying Christian’s DNA variant as a VUS in 2007 was incorrect per these same DNA variant classification criteria: “Variants of unknown significance are DNA sequence variants that are detected reproducibly, but have not been correlated with clinical presentation and/or pathology in the current literature.”

At the hearing Athena’s lawyer argued that “the patient that is identified (in Berkovic et al., 2006 and Harkin et al., 2007) as having the same genetic mutation” had, in both papers, a de novo” mutation. That is, the mutation was not inherited but instead arose during cell division of egg or sperm or early embryonic development. The defense further contended that parental testing is required to determine whether a mutation is de novo, and thus “within the classification that was in those two published reports because the patients in those reports had a de novo mutation.” According to this argument, Athena has no way to know “whether or not this serious disease is present in this mutation unless we test the parents.” The lawyer’s point was that Athena could not have known whether Christian’s mutation was de novo—and thus the same as the mutation in the published papers—because his parent did not undergo genetic testing. As noted above, however, Williams contends that, because she was unaware of the June 2007 report, she was unaware that testing of the biological parents (de novo determination) was recommended.

Athena’s lawyer pointed to patient #15 on Supplement Table 2 of Harkin et al., 2007 (a female who possessed the same mutation as Christian whose mutation was confirmed to be de novo) to illustrate that a conclusive diagnosis could be reached only by additional parental testing and de novo determination. It is intriguing that the next patient listed (#16), along with thirteen other patients on this table, had the same classification as patient number #15 but de novo status was not determined. According to Harkin et al., 2007, “in cases with missense changes, where DNA from parents is unavailable…the case for pathogenicity rests on circumstantial evidence provided by evolutionary conservation of protein structure.” Further, if parental testing was never done on Christian because his parents were unaware of this recommendation, and de novo determination was required for the DNA variant to be classified as a “known disease-associated mutation,” it is hard to understand how and why his DNA variant was reclassified to a “known disease-association mutation” sometime after the June 2007 report and before September 29, 2014…

Judge Seymour wanted to know why the 2007 report was revised. Athena’s lawyer said that “there was an update to the classification of the mutation in Athena’s database,” and that “as soon as the information became known that it was applicable to this situation, the update was provided to the requesting individual.” Athena’s lawyer further explained,

“the plaintiff’s genetic counselor called Athena in 2014 and asked Athena to re-look up the variant. Athena did so and saw that the variant, the mutation, had been reclassified since then in its database, and based on additional information that was available since June of 2007—remember, this is an incredibly fast-paced field—more than seven years later when the variant was looked up in the database to see how it’s classified. Classifications of variants do change based on new information, and that is what happened here. It’s not a reclassification based on an error. It was just based on new information” [Of note, according to the complaint, Athena was contacted in 2014 to in order to obtain the 2007 report for the first time, not to “re-look up” a variant.]

Athena’s lawyer did not explain what “new information” was obtained between June 2007 and September 2014 that resulted in the reclassification of Christian’s DNA variant (1237T>A, Y413N) from a “variant of unknown significance” to a “known disease-associated mutation.” According to the January 2015 report, “analysis of this individual’s SCN1A gene identified a DNA sequence variant that has been reported in the literature to be associated with SMEI or SMEB, the severe phenotypes associated with SCN1A mutations.”

https://theprivacyreport.com/2017/01/26/williams-v-athena-motion-to-dismiss-hearing-sc-supreme-court-may-be-asked-to-decide-whether-a-diagnostic-laboratory-qualifies-as-a-healthcare-provider/