Missed diagnoses and misdiagnoses

We hear a lot about missed diagnoses in genetic medicine, these days. We hear much less about misdiagnoses, but this will likely change.

These have become pressing considerations because cheap DNA sequencing has led to many more genetic tests being done, and has created many more options for how it can be done.


Choices, choices, choices

When performing genetic testing we are now faced with choices about how much of the genome to sequence and how to prioritise that sequencing. For example should we sequence a few genes, a few hundred genes or all genes? Should we do a restricted test of the most likely culprits first and then progress to more sequencing, or do whole genome sequencing upfront?

The problem is there is no ‘correct’ choice that fits every situation.


Missed diagnoses in genetic testing

How likely a given testing strategy will lead to a ‘missed diagnosis’, has become an over-riding consideration for many. Of course it is important. It is also very emotive. The internet is brimming with stories of families for who conventional gene testing failed to give a diagnosis, and whole genome sequencing succeeded.

A cursory evaluation of this area could lead one to assume it is always better to do a test that covers more of the genome. But this is over-simplistic. Tests targeting genes are usually faster and cheaper than whole genome sequencing. Targeted gene tests can usually be done at higher volume and throughput. Often the genes assessed in a targeted test are more comprehensively interrogated than in a less targeted test.

In some situations, these considerations are very relevant, and a staged testing strategy is appropriate. In other situations, it may be more efficient to do whole genome sequencing upfront.


Misdiagnoses in genetic testing

There are, unfortunately, several ways in which genetic tests can lead to misdiagnoses and/or mismanagement. The most direct is when someone is given an incorrect genetic diagnosis, based on a test result.

We need to be more vigilant in identifying genetic misdiagnoses and more focused in reducing them.

One of the main aims of the TGMI is to address this type of misdiagnosis, starting with a careful top-level review of which genes are robustly linked to genetic diseases, to build a reliable gene-disease map (GDM). As we discussed in a previous post, the knowledge base underpinning the foundations of genetic medicine is unreliable. This can make it difficult to answer basic questions, such as do mutations in this gene cause disease?


Misdiagnoses due to misinterpretation of the impact of specific gene variants also occur, even in genes that are definitively linked to disease. In a previous post we highlighted an example of this type of error, and its impact, in the cystic fibrosis gene.

Gene variants previously assumed to be pathogenic are increasingly being shown not to cause disease after all. Many variants, that we now know are too common in the population to cause the diseases they were linked to, are currently being reclassified. Reclassification of many other gene variants will also be required, as there has been extensive over-estimation of the likely clinical impact of rare gene variants.


Consequences of genetic misdiagnoses

The consequences of genetic misdiagnoses can be substantial and serious. For the patient, it may lead to inappropriate management and/or misinformation about prognosis.

The impacts may also affect the wider family. Genetic diagnoses in children can influence parents’ reproductive choices. Families may choose not to have any more children, as we highlighted in a previous blog. Even more worryingly, parents may undertake prenatal testing and choose to terminate a pregnancy that has been incorrectly predicted to be at risk of a genetic disease.

Another example is in cancer genetics. Some people have had ‘predictive testing’ for a BRCA variant that has incorrectly been assessed as giving, or possibly giving, a high-risk of cancer in their family. A substantial proportion of these healthy people elect to have surgery to remove their breasts based on the genetic information.

These avoidable harms are clearly unacceptable. We need to be more vigilant about the potential for misdiagnoses, more exhaustive in identifying their potential negative impacts and more focused on reducing them.


No test is 100% successful

We should not expect genetic tests to be 100% accurate. But we should expect clarity about what a test is capable of, how well it performs and what its limitations are.

More discussion and transparency about the capabilities and limits of genetic testing would be very helpful, both with respect to missed diagnoses and misdiagnoses.

No genetic test can be successful in all cases. There is too much complexity, both in how genomic alterations cause disease and in the practical processes of detecting and interpreting them. We need to acknowledge and accept this. And we need to communicate it to patients.

We should not expect our tests to be 100% accurate. But we should expect clarity and detail about what a test is capable of detecting, how well it does it, and what its limitations are. All too often this information is not readily available, or not available at all.

Recognising and openly addressing the complexities and limitations of genetic testing is key to the delivery of genetic medicine.