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Q&A: Birmingham Women's Hospital's McMullan on the Adoption of Chromosomal Microarrays in the UK

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Name: Dom McMullan

Title: Head of Molecular Cytogenetics, West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust

Background: McMullan is a clinical scientist with 20 years experience. He represents the UK on the International Standards for Cytogenomic Arrays consortium's steering committee.

Chromosomal microarrays continue to advance into routine clinical use, from the US, where they are already considered the standard of care for diagnosing constitutional abnormalities, to Israel, where the government recently began subsidizing CMA for high-risk pregnancies (BAN 5/8/2012)

But what about the UK? According to Dom McMullan, head of molecular cytogenetics at West Midlands Regional Genetics Laboratory, the availability of CMA in Britain is "somewhat patchy," with some regional labs leading others when it comes to the new technology.

McMullan's lab, located within Birmingham Women's NHS Foundation Trust, is certainly busy. He told attendees at an Affymetrix workshop at the European Society of Human Genetics meeting, held in Nuremberg, Germany, last week that his lab expects to process 42,000 samples this year in four main categories: developmental disorders, prenatal diagnosis, hematology, and molecular pathology. On the array front, the lab has for the last six months been validating Affy's CytoScan HD platform for constitutional cytogenetics. It is also working with Affy and other partners to develop an array-based approach for tumor profiling (BAN 6/14/2011).

BioArray News spoke with McMullan about his activities following his presentation at ESHG. Below is an edited transcript of that interview.


How would you describe the uptake of chromosomal microarrays by UK genetics labs?

I think it is fair to say that the uptake of arrays within the [National Health Service] is somewhat patchy. It depends on the commissioning systems in place in different regions. So there are several regions using arrays as a frontline for all suitable pediatric referrals, but the majority of centers are still processing arrays for patients referred or gatekept by clinical geneticists. This is unfortunately a continuing problem because of the funding situation in the NHS as a whole and the changes planned to the commissioning system.

Is there a regional disparity? Maybe someone in your lab is getting better treatment than someone elsewhere?

Yes, there is certainly a regional disparity due to the commissioning systems, which have differed between regions, as commissioning has been delivered by different Specialist Commissioning Groups. In the West Midlands genetics has traditionally been funded by block contracts with specialist commissioners. In general, commissioning has lacked expertise and often been quite conservative. There is a lack of funding for arrays, and it has been difficult to persuade comissioners of the necessity for array CGH as a routine, frontline test that will save significant amounts of money for the healthcare system downstream through the process of diagnosis early on in a patient pathway.

For what indications have you introduced array-based testing in your lab?

So, the intention so far for array-based testing has predominantly been for children diagnosed with developmental disorders, historically analysed using karyotyping and targeted mutation tests, such as fluorescence in situ hybridization and MLPA. We are also looking to introduce array CGH for abnormal ultrasound scans in the prenatal diagnosis setting following our experience with this in a research context. Another key area that we are looking at is the application of arrays in molecular pathology, particularly using [molecular inversion probe] arrays as part of a collaborative project with Affymetrix, Leeds University, and Almac Diagnostics in Belfast. This will be looking at over a thousand common tumors each over a two-year period to assess the utility of the MIP arrays, both for picking up common point mutations that can be used to inform targeted treatment, and also looking to leverage loss of heterozygosity and CNV data on tumors, which was previously not very easy because the majority of samples are formalin fixed and paraffin embedded.

Where are you in that process?

The project is likely to commence in earnest in September.

On the prenatal side, I hear two perspectives: Some say we should judiciously adopt the technology as a first-tier test, others worry about how to report findings of unclear clinical significance to couples. Where do you stand?

It is certainly a very difficult predicament. In the UK, we are looking to adopt array CGH only in pregnancies with an abnormal ultrasound scan and we have locally just finished a project with Birmingham University of over 200 such cases. There is a larger national project about to commence that will look at the utility of arrays versus karyotyping over a two-year period. This is a seven center study funded by the [National Institute for Health Research]. A steering committee has been set-up [to decide] which CNVs will not be reported back to parents. This project is likely to inform best practice in the UK moving forward. Reporting findings of unclear clinical significance has been a difficult area since the introduction of prenatal diagnosis by chromosome analysis. It is not really a new problem, just likely to be more common with use of arrays and at a different level of resolution.

You are using a very high-resolution SNP array platform. Some prefer CGH+SNP arrays, others are still using bacterial artificial chromosome arrays. Why did you decide to use a SNP array?

The choice of the array is very dependent in the UK on funding, and the most popular array used, the mostly widely used, are undoubtedly Agilent multiplex-based arrays – the 4x180K, the 8x160K – probably because they are viewed as being cost effective. However, in limited cohorts we have recently explored using the Affymetrix CytoScan HD, and it is clear that regions of homozygosity associated with copy number variants give additional data. In addition it gives us copy number neutral loss of heterozygosity, which can be important and a powerful tool for autozygosity mapping which is particularly relevant in a population such as the West Midlands with a large Asian population in which first cousin marriage is common, particularly in the Pakistani community. But cost is a major driver.

There have been several sessions at this meeting concerning next-generation sequencing-based diagnostics, but most have not discussed the use of sequencing in clinical cytogenetics. Do you have an interest in using sequencing in the future?

Undoubtedly, sequencing will replace arrays for looking at copy number. But I think it is fair to say that there is a general consensus that sequencing is not a mature enough technology to get reliable copy number data for clinical diagnostics yet, although some groups are looking at doing so. In time, I think there will be a pragmatic approach whereby children with developmental disorders will be first screened by array, and then those who are negative will go on to exome sequencing. I think that eventually whole-genome sequencing will replace the entire system. It is difficult to say when that could happen, because sequencing technology is developing all the time. It is possible that the technology that we will eventually do this may only just have been invented.

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