Improved genetic diagnosis of Multiple Endocrine Neoplasia type 1 by next generation sequencing of the entire MEN1 gene
Clinical Scientist, Martina Owens (The Royal Devon & Exeter Hospital’s Molecular Genetics Centre)
Multiple Endocrine Neoplasia type 1 (MEN1) is caused by mutations on the MEN1 gene, which is located on chromosome 11. The mutations identified to date are mainly located in the regions of the gene that code for the Menin protein. However, in some families with MEN1 a mutation has not been found. This suggests that they have a mutation in a part of the MEN1 gene that has not been tested or they have a mutation in another gene that has not been shown to cause MEN1 yet. In some genes causing other disorders, mutations have been found deep within the introns (the non-coding regions of the gene not routinely tested). These mutations prevent the production of functional protein. Improvements in DNA sequencing technology mean that we are now able to test the whole gene region (>11,000 bases) rather than just the coding parts (~1,830 bases).
This project involves testing unrelated patients who have a clinical diagnosis of MEN1 but in whom a mutation has not been identified to determine whether they have a mutation in the non-coding regions of the MEN1 gene. Finding a mutation will provide a genetic diagnosis and enable pre-symptomatic testing for relatives. The results of this study will determine the need to adopt this as a new genetic diagnostic test for MEN1.
After studying for a degree in Forensic science at the University of Teesside where she developed an interest in genetics, Martina went on to do a Masters degree in Molecular Biology at the University of Hertfordshire.
Martina took up a post at the Exeter lab in 2000 where she completed her training as a Clinical Scientist in Molecular Genetics. In 2001 she received a small grant from the Royal Devon and Exeter NHS Foundation Trust to undertake dosage analysis to look for deletions/duplications in the MEN1 gene in patients in whom no mutation had been identified. Martina is now a Registered Clinical Scientist overseeing the Multiple Endocrine Neoplasia service in the Exeter lab.
Martina responded that she is “…thrilled that my project was chosen to receive this award. Our laboratory has a number of families with MEN1 in whom we have not found the genetic cause. This funding will enable us to go back and, using the latest technology, look in more depth at the MEN1 gene.”
We congratulate Martina on her Research Award of £9,910 from AMEND for this valuable project and look forward to hearing about the progress and results in the future.
6-month Progress Report:
‘A search of all patient samples that had previously been sent to our laboratory for genetic testing for MEN1 was carried out to identify patients who did not have a mutation in the MEN1 gene. This identified:
– 52 patients with MEN1 and had relatives who are also affected with MEN1 (familial cases)
– 244 patients with MEN1 where no one else in their family was affected (sporadic cases).
A letter was sent to these patients’ clinicians to ask for consent to include their DNA samples in this project. To date, consent has been obtained for 76 patients. We designed an assay to test the entire MEN1 gene (previous testing only looked at the parts of the gene that contain the code for the Menin protein).
Testing has been completed for 28 patients so far. The new test has found a mutation in two patients that we could not detect using the original test method. Testing is now possible for their relatives in order to find out their risk of developing MEN1. In two further patients we found DNA changes that need further investigation to determine whether they cause MEN1 and this work is progressing well.’
Martina Owens (13 February, 2015)