While people carry mostly the same genes, there are small differences in the sequences of those genes that can have profound effects on health. Some genetic variants have been linked to a greater (or lesser) likelihood of developing some diseases. Genetic testing that looks for such disease-related genetic variants is becoming more common, but new work has suggested that some of those tests are not reliable. The work, which indicated that most of the time tests are telling people that they carry very rare variants, those people actually do not carry them, has been reported in BMJ.
The scientists began this study after learning of cases in which women scheduled preventative surgery because they'd been told they carried a breast-cancer-linked rare variant in the gene BRCA1. Mutations in BRCA1 are known to significantly raise the risk of breast cancer - when women are actually carrying them. When the researchers examined the results from genetic testing of almost 50,000 people in the UK Biobank and a group of commercial consumers and compared them to genomic sequencing that is far more reliable, the researchers found that the tests were wrongly alerting people to the presence of very rare variants in the majority of cases.
The genetic tests utilize SNP chips, which examine variations in the sequence of the genome at thousands of places. While SNP chips are very good at detecting common genetic variants that are linked to disorders like type 2 diabetes, it's been known among the research community that they aren't very reliable at finding rarer variants. However, consumers that use commercial tests that are widely available aren't as likely to be aware of this problem.
"SNP chips are fantastic at detecting common genetic variants, yet we have to recognize that tests that perform well in one scenario are not necessarily applicable to others. We've confirmed that SNP chips are extremely poor at detecting very rare disease-causing genetic variants, often giving false-positive results that can have profound clinical impact. These false results had been used to schedule invasive medical procedures that were both unnecessary and unwarranted," explained senior study author Caroline Wright, Professor in Genomic Medicine at the University of Exeter Medical School.
The study indicated that common variants are reliably detected, but that reliability decreases as the genetic variant becomes rarer. Known, very rare genetic variants are found in fewer than one in 100,000 individuals. This work found that 20 of 21 commercial customers that were tested, and 84 percent of people in the UK Biobank had gotten false positives regarding rare variants that cause disease.
"The number of false positives on rare genetic variants produced by SNP chips was shockingly high. To be clear: a very rare, disease-causing variant detected using a SNP chip is more likely to be wrong than right," said study co-author Dr. Leigh Jackson, Lecturer in Genomic Medicine at the University of Exeter.
"Although some consumer genomics companies perform sequencing to validate important results before releasing them to consumers, most consumers also download their "raw" SNP chip data for secondary analysis, and this raw data still contain these incorrect results. The implications of our findings are very simple: SNP chips perform poorly for detecting very rare genetic variants and the results should never be used to guide a patient's medical care, unless they have been validated."