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Reading reports

In this video, we will look at the information given by a genetic report, and how to understand the results in the report in clinical practice
We’re now going to consider the different types of genetic test report which you may receive in clinical practice. The different types of genetic test results which they may contain. This is a schematic of a generic test report and in practice, each individual lab will issue their reports in different ways. However, there will be information common to all which is essential for correct interpretation of the report. We’re going to consider two main types of report. Firstly, an array CGH report, which gives us information about copy number variation in the chromosomes. Secondly, a molecular test report, which gives us information about mutations identified or not within the DNA sequence.
Some information will be common to all reports– the referrer’s identifying details and the patient’s identifying details. Information about the sample type is particularly important. Usually DNA is extracted from peripheral blood samples, but mouth swabs or skin biopsies may also be the source of the patient’s DNA, amongst others. Genetic tests can be undertaken on tumour tissue or samples from invasive prenatal testing, such as a CVS or amniocentesis. It is therefore important to confirm the sample type as what you’re expecting. The genetic results may be different depending on the DNA source. Let’s now consider the referral reason and type of test being undertaken.
We have discussed the different types of genomic tests available during this week, and we have also discussed which tests are best in different chemical scenarios. Array CGH is usually the first line test for children with developmental disorders. For example, developmental delay in combination with other congenital abnormalities. For molecular tests, a number of different referral scenarios are possible. The test may be undertaken to perform predictive testing for a mutation previously identified in the family. In this case, the test will only screen for the familial mutation. It will not look at the rest of the gene and it will not look at any other genes in the genome.
The test may be undertaken to try to diagnose the cause for a patient’s condition. This can involve undertaking DNA sequencing of a single gene, or two genes, with additional MLPA testing to look for gene deletions or insertion mutations. Or the test may involve using next generation sequencing to look at panels of genes. In any of these cases, the test being undertaken should be clearly specified. It is important to know which test has been undertaken, as not all mutations are picked up each test. For example, an array CGH will not identify base substitutions in a single gene, and next generation gene sequencing panels are less sensitive at identifying complex insertion and deletion mutations.
Do not assume that a single genetic test has ruled out a genetic cause for the condition and seek further advice from a geneticist, if required. Let’s consider the possible outcomes of an array CGH test. Number one– the array CGH report may state no abnormal copy number variants were identified and that the cause for the patient’s condition has been found. As we’ve previously stated, remember the negative array CGH result does not exclude a genetic cause for the patient’s phenotype, as we have not looked mutations at the DNA sequence level. It excludes copy number variation only, to the limits of resolution of the technology and may still have missed smaller insertion or deletion variance, which were not covered by genetic probes.
Please seek further advice if you still suspect an underlying genetic abnormality. In addition, you may always want to remember to check the sex of your patient correlates with the array CGH report. Two– the array CGH report may identify a known pathogenic copy number variant. If the clinical features given by the referrer match this copy number imbalance, the report will state the CGH abnormality fits with the clinical phenotype. If not, the referrer will need to consider the clinical presentation in light of the array result The patient can be referred to clinical genetics to fully discuss the implications of this finding. Genes found within the imbalance will be listed for the referrer.
Three– the array CGH report may identify a chromosome imbalance of uncertain significance. In this case, a detailed analysis of the CNV should be undertaken in conjunction with the patient’s phenotype and family structure, possibly requiring further samples from parents and other family members. In some instances, the CNV will be an unlikely cause of the patient’s phenotype. In this example, only one gene is contained within a small duplicated area. This is most likely to be benign variation. On other occasions, the evidence will weight more in favour of pathogenicity. Large deletions containing lots of genes fall into this category. However, these types of reports should not be over-interpreted until specialist’s advice is sought, as this can lead to unwarranted distress for a family.
Let’s turn now to our molecular test reports. One– the test report may state no pathogenic mutation was identified in the genes examined and that a cause for the patient’s condition has not been found. This does not exclude the possibility that the patient has a mutation in a different gene responsible for the disorder. Further genetic testing may be indicated, or a decision may be made to manage the family on the basis of the negative test result. Two– a known pathogenic mutation will be identified in the gene examined. In this case, the cause of the patient’s phenotype has been identified, and the patient and family should be referred to geneticist for ongoing clinical management.
Three– a variant of unknown clinical significance may be identified in the gene examined. This should then be analysed by an expert. Variance of uncertain significance should be considered as non-clinically actionable, unless upgraded by a specialist. Finally, it’s important to ensure that the mutation report has been reported and authorised, and whether there is any additional information relevant to the test which must be considered. This is often found in a notes section at the bottom of the report. To end, let’s summarise the key points to consider when reading a genetic report. Check all identifying information carefully. Check sample type and test carefully, and ensure they are as expected. Be clear what the test result has excluded and what it has not excluded.
Do not over-interpret variants of uncertain significance and always seek specialist advice when necessary.

This video outlines different types of genetic reports received by clinicians, the different results they may give and what the implications of these are in clinical practice.

What are the key points to consider when reading a genetic test report?

  • Check all identifying information carefully
  • Check sample type and test carefully and ensure they are as expected
  • Be clear what the test result has excluded and what it has not excluded
  • Do not over-interpret variants of uncertain significance and seek expert advice when necessary

Talking point

Do you think a genetic report should be written so that it is primarily understood by:

  1. Only doctors who are used to reading genomic reports i.e. Clinical Geneticists?
  2. Any referrer who is clinically trained but not necessarily used to reading genetic reports?
  3. The patient?
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