The genomics multidisciplinary team meeting (MDT) in rare disease

Genomics multidisciplinary team meetings (MDTs) enable multi-professional discussion of clinical cases and genomic results for patients with rare disease.

They can be particularly helpful for discussing variants of uncertain significance (VUS, incidental findings and cases where there has been a negative result from genomic testing but clinical suspicion of a genomic diagnosis remains high.

For particularly complex results, clinical scientists may seek the advice of specialist MDTs known as Genomic Rare Disease Advisory Boards (GRDABs).

These meetings are a routine part of work in genomics, but there are some instances in which they are especially helpful.

1. Where a 'hot' or 'warm' variant of uncertain significance (VUS) has been identified

Variants that have just missed a likely pathogenic classification due to lack of evidence (so-called ‘hot’ VUSs) often benefit from discussion.

MDTs are a good forum for these discussions: they enable clinicians and clinical scientists to work together to ascertain whether any further evidence can be gathered to aid a more definitive classification of the variant.

Some questions that might be considered by an MDT include:

• Are there any phenotypic features that could result in the VUS being upgraded? Discussion of additional phenotypic detail and/or reviewing photographs with a clinical geneticist in an MDT may result in a hot or warm VUS being upgraded to likely pathogenic or pathogenic.

• Would testing of any other family members help? Testing of other family members may give us segregation data: a clearer picture of whether the variant in question is present in other family members, and how or if they are affected clinically, which may result in a more definitive classification of the variant.

• Are there any additional investigations that could help? MDT discussions can help identify when additional investigations, such as biochemical testing or additional imaging, would be beneficial to variant interpretation. Sometimes specialist genomic tests, such as mRNA studies (which can show whether a variant affects splicing) may be suggested.

2. Where an incidental finding has been identified

Where an incidental finding is identified during genomic testing, the MDT can be a useful platform for discussing the key issues of:

• what the clinical implications of the incidental finding are and how best to manage the patient; and
• whether the finding should be reported to the patient and/or their family.

The British Society for Genetic Medicine has published national guidelines to support decision-making around the return of incidental findings.

3. Where a result is negative, but there is still concern that there could be an underlying genomic diagnosis

Sometimes a genomic result comes back as negative, but there is concern that an underlying genomic cause for the patient’s condition may have been missed. MDTs can be a good forum to discuss the investigations that have been carried out for a patient and to review with both clinical and clinical scientist colleagues whether this testing was appropriate and if any further testing or analysis is likely to be informative. Useful questions to consider include:

• Has the correct test been carried out?
• Are there any other tests or gene panels that should be applied?
• Do you suspect a specific syndrome that is caused by a specific gene/set of genes that could be re-analysed to ensure nothing has been missed?

If a molecular diagnosis cannot be confirmed but your clinical suspicion remains high it may be helpful to discuss the matter further with clinical colleagues – specifically, whether the phenotypic information is sufficient to make a clinical diagnosis of a genetic condition in the absence of a molecular diagnosis.

The term MDT tends to refer to a more formal meeting of various experts, but in reality collaboration happens in many ways.

Formal MDT meetings vary from region to region. For instance, in some areas those from the laboratory and clinical genetics department have regular variant interpretation meetings, and some regions have MDTs for specific specialty groups that involve representatives from both the laboratory and the clinical genetics service in addition to specialty clinicians (for example ‘cardiac MDT’ meetings).

In formal settings like these, there may be a co-ordinator and a set framework for the discussion and recording of cases. A template may be used to support discussion of evidence for a variant classification, and to record the outcome.

In other situations, clinical scientists may seek the advice of newly established specialist MDTs known as Genomic Rare Disease Advisory Boards (GRDABs) and Genomic Tumour Advisory Boards (GTABs) when they encounter variants that are difficult to interpret. These teams have been established to offer advice on complex results.

Outside of these formal MDT gatherings, those dealing with genomic results frequently interact with other clinicians as they investigate genomic information and make joint clinical decisions. This may involve meetings but can also be done by email or over the phone.

Whatever the setting, it is important that all discussions between members of MDTs are appropriately recorded in the patient’s notes.

• Remember that different members of the MDT will have different professional and scientific backgrounds and knowledge, so reduce the use of jargon where possible.
• Foster a non-judgemental and supportive atmosphere in which questions are encouraged.
• Circulating cases for discussion ahead of MDT meetings allows members to prepare and can result in more informed and productive discussions.
• Ensure systems are in place to record MDT discussions appropriately in patient notes.
• In genomics, there are often several reasonable courses of action. Identifying the best one for a patient relies on understanding the patient’s and/or family’s perspective, as well as the clinical picture.

• The genomics MDT provides a useful forum to discuss clinical cases and complex results for patients with rare disease.
• It can be particularly valuable for discussing variants of uncertain significance, incidental findings and unexpected negative results.
• MDT discussions and their outcomes should always be appropriately documented.

Resources for clinicians

• The British Society for Genomic Medicine (BSGM): Guidance on Incidental Findings
• NHS England Genomics Education Programme (GEP): Careers in genomics