Presentation: Patient needing parental genetic blood samples after child’s microarray result
If a microarray test reveals copy number variants, parental genomic testing of the variants can potentially aid diagnosis and could be used to predict future recurrence.
At a glance:
- A microarray is often one of the first-line genomic tests in intellectual disability. It identifies changes in amounts of genetic material – for example, duplications, deletions and unbalanced rearrangements, known as copy number variants (CNVs). The significance of these changes can be uncertain.
- Parental testing can aid interpretation of the possible significance of a CNV and, if a CNV is considered to be contributing to a child’s condition, can provide information about the future chance of recurrence.
- CNVs can vary in presentation even within the same family. It is not uncommon to identify a CNV in a seemingly unaffected parent after a diagnosis is made in their child.
- Alert! Genomic testing should not be performed without a prior discussion about the possible implications for both the patient and their wider family.
Example clinical scenario
You see a couple with their six-year-old son. He has global developmental delay and his recent microarray test revealed a 16q11.2 microduplication. The parents have received a letter from the paediatrics team requesting a referral to clinical genetics to arrange genomic testing for the microduplication. They are also keen to know if any future children may be affected.
Identifying those at risk of a genetic condition
- A microarray identifies submicroscopic changes (such as CNVs) in the amount of an individual’s genetic material, as well as anomalies in numbers of chromosomes (aneuploidies), such as trisomy or monosomy.
- Some microarray results may identify CNVs that are well documented as pathogenic and fit well with the patient’s clinical features, allowing a diagnosis to be made.
- Other microarray results may be of uncertain significance, with little to no information to clarify the clinical significance of the variant on the patient’s clinical features.
- Inherited microdeletions and microduplications usually follow an autosomal dominant pattern. Testing the parents can identify whether the variant has arisen de novo in the child or has been inherited from one of the parents. This is important for the following reasons.
- To aid prediction of recurrence. For example, if the variant is de novo in the affected child, the likelihood of recurrence in a subsequent pregnancy is extremely small.
- To provide further clarity to the significance of the variant if this is unknown. For example, if an unaffected parent shares the same variant as a severely affected child, this may indicate that the variant is a benign CNV that is less likely to be contributing significantly to the affected child’s phenotype.
- If the same finding is identified in a parent, a conversation can be had about whether they have also experienced difficulties relating to the variant, and support and appropriate clinical management can be provided (although there are very limited adult-onset complications).
- Several recurrent CNVs that confer an increased risk of neurodevelopmental conditions (neuro-susceptibility loci) have been identified. It should be noted that antenatal testing is generally not offered in this context due to the widely variable expressivity and heterogeneity of the associated clinical features, with carriers ranging from asymptomatic to significantly affected.
What should you do next?
- Arrangements required for any onward referral and consent processes for the investigation and the taking of the sample may vary, so refer to local pathways. If onward referral is needed, include details of the affected child in the referral letter.
- Provide ongoing support and clinical care to the child and family. The charity Unique provides helpful and comprehensive patient resources detailing potential clinical features for all CNVs.
Resources
For clinicians
- NHS Genomic Medicine Service: Record of discussion regarding genomic testing
- Unique (Understanding rare chromosome and gene disorders)
- Unique (Understanding rare chromosome and gene disorders): Microarray-based comparative genomic hybridisation (downloadable leaflet)
For patients
- Manchester University NHS Foundation Trust: A microarray test: Information for patients (downloadable leaflet)
- Unique (Understanding rare chromosome and gene disorders)
- Unique (Understanding rare chromosome and gene disorders): Microarray-based comparative genomic hybridisation (downloadable leaflet)