Identifying protective mutations through comprehensive genetic screening gives litigators more leverage to argue disease causation in court. Protective mutations are certain altered points in an individual’s DNA that can give them robust resistance to developing disease even if exposed to a known causative agent. Accordingly, if genetic testing shows that a particular person harbors resistance mutations, there is data to rely on to support the argument that a particular person’s disease was not caused by an “exposure.”

For example, in one recent ToxicoGenomica case, a claimant cited occupational benzene exposure as the cause of their acute myeloid leukemia (AML) and argued that they could be more susceptible to developing a disease after an “exposure”. However, that argument failed when a comprehensive genetic analysis of the claimant’s DNA was performed. Specifically, it turned out that protective mutations were identified that actually gave the individual more robust resistance to the toxic effects of benzene, thereby effectively ruling out the claim that occupational exposure could have caused this individual’s AML. Finding that an individual is genetically resistant to the type of exposure in question is a remarkably effective tool in demonstrating a particular disease was not caused by an “exposure”, or the disease in question was caused by another toxicant unrelated to a specific claim.

While some individuals have resistance to environmental hazards, others may be protected against specific genetic diseases. These types of mutations are suspected in many genetic diseases, and a number have been identified definitively. In our previous blog post, we discuss a newly identified protective genetic mutation that conferred resistance to ALS development. Other neurological heritable diseases with identified protective mutations include Alzheimer’s and Parkinson’s disease.

The range of protection can vary. For example, there’s a category of individuals that experience something called asymptomatic or preclinical Alzheimer’s disease. While these individuals have all of the neuropathological hallmarks of the disease, they experience no cognitive impairment–and research is identifying certain genetic protective mutations that prevent that cognitive decline from ever occurring. One single-nucleotide polymorphism (a mutation type in which just one nucleotide is changed) in the amyloid precursor protein (APP) gene, for example, affects largely a Nordic population. While this is an uncommon mutation, it protects comprehensively against genetic Alzheimer’s development and age-related cognitive decline in general. In the APP gene alone, there are 25 identified mutations that modulate the pathogenicity of Alzheimer’s disease–and one systematic review found 10 other genes of interest involved in Alzheimer’s disease, each with multiple different mutations that can change disease outcomes.

Protective mutations come in many shapes and sizes. Some occur in genes themselves, but others happen in the vast regions of non-coding DNA that make up most of a person’s genome. To best inform a legal argument involving a disease with known protective mutations, whole-genome sequencing (WGS) is the optimal choice because it covers the non-coding DNA, unlike whole-exome sequencing. Accordingly, WGS provides the most comprehensive view of a genetic disease and may provide data to support causation arguments.