On 5th January 2008, a two-year old boy called Christian Millare had a severe seizure and died. Eight years later his mother Amy Williams, has filed a lawsuit in the fifth judicial court in Richland County, South Carolina. Williams alleges that because Athena Diagnostics (a subsidiary of Quest Diagnostics – one of the largest reference labs in the US) 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.
Christian began having seizures aged 4 months old and as his seizures worsened he underwent endless tests to understand his condition. Results showed that a mitochondrial disorder may be causing the seizures and so he was treated with increasing doses of the sodium channel-blocking drugs carbamazepine and lamotrigine, which are standard treatments for epileptic seizures that are not due to Dravet syndrome. Christian’s autopsy report states that he died due to complications from an unspecified mitochondrial disorder.
In 2007, a sample of Christians blood was also analysed at Athena Diagnostics for mutations in the SCN1A gene. Mutations in the SCN1A gene are well known in the literature to cause Dravet syndrome, a severe form of epilepsy that impacts one in 21,000 infants. Studies show that sodium channel-blocking drugs like carbamazepine and lamotrigine worsen seizures in Dravet patients. Athena Diagnostics classified Christian’s SCN1A mutation as a variant of unknown significance (VUS), meaning the lab determined there was insufficient evidence in 2007 to link his mutation to epilepsy or determine it was benign.
In the lawsuit Williams has brought against Quest Diagnostics, Williams accuses Athena of misclassifying her son’s SCN1A mutation as VUS when there was enough evidence in the literature at the time to show it was disease-causing. Further, 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.” In 2014, Williams discovered that Athena had now reclassified the SCN1A mutation Christian had as disease-causing. In 2015 the lab issued an amended report for Christian but the published studies listed as the evidence used to make the variant classification were the same in the amended report as in the original 2007 report. Williams herself underwent genetic testing after publication of the amended report and found she does not have an SCN1A mutation or mitochrondrial defects.
The lawsuit lists Athena’s failure to provide additional information to support this variant reclassification as one of the many violations of the Clinical Laboratory Improvement Amendments (CLIA – the federal regulatory standards that all labs must follow when testing humans).
Robert Cook-Deegan, an expert in genomic testing policy and ethics at Duke University filed an affidavit on behalf of the plaintiff stating his opinion that Athena breached the standards of care for a high-complexity genetic testing lab. He stated that this case exposed “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 it way into public databases for others in the field to evaluate and makes its way to providers’ and patients’ hands. Cook-Deegan wrote in his affidavit that Christian’s final and fatal seizure in January 2008 was due to Athena’s “negligent diagnosis and failure to accurately advise selection of appropriate therapy.”
This ongoing case has highlighted the need for more accessible public genetic variant resources. ClinVar is an NIH-funded database launched in 2013, where labs can submit variant interpretations. The Clinical Genome Resource (ClinGen) is another initiative to create a shared knowledgebase of genes and genetic variants important to human health. There are also now databases dedicated to SCN1A mutations, which list the SCN1A mutation Christian had as causing Dravet syndrome.
Further, the FDA are currently preparing to finalise guidelines for regulating lab-developed tests (LDTs), like the SCN1A test, which are currently regulated under CLIA. The FDA stated that the CLIA is not sufficient to protect the public’s health and have issued a report highlighting 20 cases where tests not overseen by the agency have caused harm. Also the FDA’s work in developing and defining best practices for databases used for clinical interpretation of variants is aiding the dissemination of this important knowledge.
This work has come too late for Christian Millare but generations to come will benefit from these increasingly regulated shared genetic variant resources.
- Vickie Flint PhD
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