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Challenges of array CGH interpretation in clinical practice

The introduction of any new technology into routine clinical practice brings with the benefits new challenges that need to be addressed but also that may not have been anticipated.

The purpose of array CGH analysis is to report only those findings that definitely explain or are highly likely to explain the presenting symptoms and signs of the patient.

However other scenarios may arise.

  • CNV of uncertain significance

Due to the high resolution of the test we may identify copy number variations (CNV) of uncertain significance.

The challenge here is to prepare patients and their families in advance that we may find CNV(s) of uncertain clinical significance, but also to explain that this is an evolving field and we are constantly learning about the degree of genetic variation in humans.

For that reason, our interpretation of such CNVs may change in the future and patients will be contacted if appropriate. This uncertainty can cause anxiety for patients and families thus counselling them in advance of this potential outcome is important.

  • CNV of variable penetrance

Array CGH has revealed that there exist a significant number of neurosusceptibility loci (regions) that lower the threshold for manifesting intellectual difficulties, autistic spectrum disorder, and developmental delay.

When identified in a child presenting with such symptoms one of the parents is often found to carry the same CNV but does not have a history of symptoms. This is known as reduced penetrance and it is presumed that additional factors are required to cause the symptoms to manifest.

  • Incidental findings

Infrequently, the testing may identify a clinically significant deletion or duplication that is not the cause for the presenting symptoms in the patient but may have implications for their future health and, if inherited, for the health of their relatives.

An example of this would be deletion of a cancer predisposition gene. Such results are fed back to patients so that they can be counselled about screening programmes or prophylactic surgery.

Despite some of these difficulties, for those of us in the practice of clinical genetics and paediatrics, this test has allowed us to give many more families an explanation for their child’s difficulties.

Although curative treatment may not be possible this allows us to give information on the natural history of the condition to the family which can be “therapeutic” and assists in devising a management and educational strategy to support the child’s growth and development.

Talking point

Geneticists often use numbers to try to help patients understand genetic test results. For example, when discussing a CNV of variable penetrance, they might tell a parent, “40% of people with this CNV have autistic features and/or learning difficulties, and 20% have heart defects”.

What do these figures mean to you? Would you perceive them as high risk or low risk?

What other information might you need to process these risks in a way that makes sense to you?

Can you think of any strategies you could use to explain risk to patients with low numeracy levels?

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The Genomics Era: the Future of Genetics in Medicine

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