Skip to 0 minutes and 7 secondsWe are now going to consider the different types of genetic test report which you may receive in clinical practice and the different types of genetic tests 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 are going to consider two main types of report. Firstly, an array CGH report which gives us information about copy number variation in the chromosomes. And, secondly, a molecular test report which gives us information about mutations identified or not within the DNA sequence.

Skip to 0 minutes and 57 secondsSome 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. And these genetic tests can also 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 is what you are expecting, as genetic results may be different depending on the DNA source. Let's now consider the referral reason and type of test being undertaken.

Skip to 1 minute and 48 secondsWe have discussed the different types of genomic tests available during this week, and we have also discussed which tests are best in different clinical 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.

Skip to 2 minutes and 42 secondsThis could involve undertaking DNA sequencing of a single gene-- or two genes-- with additional MLPA testing to look for gene deletion or insertion mutations.

Skip to 2 minutes and 55 secondsOr, 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 by each test. For example, an array CGH will not identify base substitutions in a single gene, and next-generation gene sequencing panels is less sensitive at identifying complex insertion-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.

Skip to 3 minutes and 39 secondsLet us consider the possible outcomes of an array CGH test. Number one, the array CGH report may state no abnormal copy number imbalances were identified, and that a cause for the patient's condition has not been found. As we have previously stated, remember that a negative array CGH result does not exclude a genetic cause for the patient's phenotype as we have not looked for 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 variants which were not covered by genetic probes. Please seek further advice if you still suspect an underlying genetic abnormality.

Skip to 4 minutes and 29 secondsIn addition, you may always want to remember to check that the sex of your patient correlates with the array CGH report.

Skip to 4 minutes and 38 secondsTwo. 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 that 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, and the genes found within the imbalance will be listed for the referrer. Three. The array CGH report may identify a chromosome imbalance of uncertain significance.

Skip to 5 minutes and 24 secondsIn 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 a specialist's advice is sought as this can lead to unwarranted distress for a family.

Skip to 6 minutes and 17 secondsLet'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 a geneticist for ongoing clinical management. Three.

Skip to 7 minutes and 3 secondsA variant of unknown clinical significance may be identified in the gene examined. This should be then analysed by an expert. Variants of uncertain significance should be considered as non-clinically actionable unless upgraded by a specialist. Finally, it is 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 note 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.

Skip to 7 minutes and 58 secondsDo not over-interpret variants of uncertain significance, and always seek specialist advice when necessary.

Reading Reports

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

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The Genomics Era: the Future of Genetics in Medicine

St George's, University of London

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