The team behind a new study has found that many pathogenic genetic variants have a low risk of causing disease. These findings may change the way genetic testing results are interpreted in the future.
Pathogenic variants and disease
For years now, scientists have known that certain genetic variants can increase the risk of an individual developing diseases. Genetic tests are often used in clinical settings to identify whether an individual is carrying any pathogenic genetic variants.
However, for most pathogenic genetic variants we don’t know to what extent they increase the risk of developing an associated disease. This has created many issues in terms of making diagnoses and communicating results to patients.
To try and solve this problem, the team behind a new study, published in JAMA, analysed the genomic and health data of thousands of individuals.
Calculating disease risks
First, the team analysed DNA sequencing data from 72,434 individuals for 37,780 known pathogenic or loss-of-function variants. Next, they scanned the health records of each individual for any disease diagnoses corresponding to the variants. The results revealed links between 157 diseases in the dataset to 5,360 known variants. The team then calculated the penetrance of these variants (the chance that the variant was linked to a disease diagnosis).
Overall, the average penetrance of the pathogenic variants was relatively low – only around seven percent. Therefore, the team deemed the majority of the variants identified in this study unlikely to cause disease in the individual carrier.
Despite this, not all variants had low penetrance. The team found that two breast cancer-associated variants, BRCA1 and BRCA2, had a 38% chance of being linked to a disease diagnosis. In addition, variants that were classed as both pathogenic and loss-of-function had higher penetrance than those that were pathogenic but not loss-of-function.
Interestingly, the team also found that some variants were only present in individuals of specific ethnicity. For example, out of 3,408 pathogenic or loss-of-function variants in the UK Biobank data, 11 were only present in individuals of Asian ancestry and 235 were only present in individuals of European ancestry. Some of these specific variants also had relatively high penetrance, such as an Asian ancestry specific variant associated with thalassemia. These results emphasise the importance of having a diverse study cohort.
Until now, studies investigating variant penetrance have used small cohorts usually consisting of individuals with family history of disease. Using such cohorts has been shown to over-estimate disease risk. The current study has addressed the pre-existing biases by using a large cohort representative of the general population.
Overall, the results revealed that most pathogenic variants had low disease risk. These findings raise the question of whether such variants should be classified differently to reflect the low penetrance. The researchers suggest that taking penetrance into account will allow for better calculations of disease risk and therefore better personalised medical care.
However, this study did have its limitations. The datasets used may have been biased, so in some cases penetrance levels may have been under-estimated or over-estimated. Despite this, the study represents a big step forward in determining the true risks of variants.
Senior author, Dr Ron Do, said:
“While more research is needed to be done, we feel that this study is a good first step towards eventually providing doctors and patients with the accurate and nuanced information they need to make more precise diagnoses.”
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