The Significance of Unknown Significance: A Teachable Moment

Jeanette J. McCarthy, MPH, PhD; Bryce A. Mendelsohn, MD, PhD


July 05, 2016

Author's Note:
A lawsuit was recently brought against Athena Diagnostics by the mother of a patient with a rare genetic disease who underwent genetic testing but died undiagnosed.[1,2] The lawsuit places blame on the diagnostic laboratory that performed the genetic testing. Some are using this opportunity to suggest the need for tighter government oversight of laboratory-developed tests.[3] Others are advocating data sharing by testing laboratories.[1] We would like to use this case to educate healthcare providers.

Key Points About the Case

The young patient had epileptic seizures of unknown origin. To facilitate diagnosis, the doctor ordered a genetic test that sequenced SCN1A, a gene in which mutations are a known cause of epileptic encephalopathy (ie, Dravet syndrome). The test results were inconclusive; a variant of uncertain significance (VUS) was found in the SCN1A gene. With no conclusive genetic evidence for Dravet syndrome, the treating physician pursued therapy for a presumed mitochondrial disorder.

Years later, in 2015, the laboratory released a new report with the variant reclassified as pathogenic (ie, diagnostic of Dravet syndrome). By this time, the patient had died.


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