C3 Lends Support to New Initiative in Genetic Testing for LGMD2A Patients

Coalition to Cure Calpain 3 is excited to announce that we are funding the MYO-SEQ project at the John Walton Muscular Research Centre at Newcastle University (UK). We are partnering with several patient organizations and biopharmaceutical companies to support this program, which collaborates with the Broad Institute of Harvard and MIT to apply whole exome sequencing to patients with unexplained limb-girdle weakness.

The initial phase of this project found that the gene for Calpain 3 was the most likely to contain a disease-causing variant in this group. This project is important because it will increase the number of genetically confirmed limb-girdle muscular dystrophy type 2A (LGMD2A) patients, and will facilitate better estimates of the number of people living with LGMD2A.

It is crucial that we know the prevalence of LGMD2A so that we can attract the attention of researchers and drug developers. Patients with limb girdle weakness and/or elevated serum creatine kinase levels who do not have genetic confirmation of their disease subtype should have their clinician contact the MYO-SEQ team at myo-seq@newcastle.ac.uk.

A MESSAGE FROM THE MYO-SEQ TEAM
The European Commission considers a disease ‘rare’ if it affects less than 5 in 10 000 people of the general population. It is estimated that there are up to 8 000 different kinds of rare diseases, which can collectively affect approximately 8% of the population; or in other words 36 million people living in the European Union alone.

Due to individual rare diseases affecting very few people, there is often an incomplete knowledge and understanding of the conditions. For example, researchers and doctors might still have questions about how many people are affected, who is affected, what the symptoms are and what treatments could work. In addition to the lack of knowledge, traditional clinical trial designs that are needed to develop therapies may be inappropriate or simply not feasible. As such, the costs of developing and marketing potential treatments, compared to non-rare disease therapeutics, are high. Overall, this means that unless large groups of affected patients can be gathered and studied, rare diseases can be very difficult to understand, investigate and treat.

Despite these hurdles, promising advances are being made in this difficult field. It is known that up to 80% of rare diseases are caused by genetic changes, meaning the sequence of deoxyribonucleic acid (DNA) is different in the affected person compared to the general population. Next-generation sequencing (NGS) is a powerful and sophisticated technology that allows the entire genetic sequence of any rare disease patient to be deciphered. One type of NGS is called whole exome sequencing (WES), and this only sequences the regions of DNA that code for proteins, the functional molecules of the cell. The benefit of WES compared to other NGS technologies is that the cost is substantially reduced without significantly compromising the value of the resulting data. This is because only 1% of our DNA is coding, yet approximately 85% of known disease-causing genetic changes can be found here.[2] By combining this sequencing information with a patient’s clinical data, it can be possible to accurately pinpoint the exact genetic position that has changed.

The John Walton Muscular Research Centre at Newcastle University and the TREAT-NMD Neuromuscular Network are involved in a number of large rare disease research consortia. One such collaboration is the MYO-SEQ project, which was established in 2014 and is funded by the industrial bodies Sanofi Genzyme and Ultragenyx, and the patient organisations Muscular Dystrophy UK, LGMD2I Research Fund, Samantha J Brazzo Foundation, LGMD2D Foundation and Kurt+Peter Foundation. The project intended to collect samples from 1 000 patients with unexplained weakness of the shoulder, upper arm, pelvic area, and/or thigh muscles – also known as the limb-girdle muscles. The aim was to perform WES for these patients in order to look for disease-causing DNA changes in a list of 169 candidate genes.

MYO-SEQ is responsible for gathering the largest cohort, to our knowledge, of patients with unexplained limb-girdle weakness. We have now collected in excess of 1 000 samples and have performed WES for 890 patients; potential disease-causing changes have been detected in 435 (49%) of the sequenced patients. Interestingly, genetic changes in CAPN3 (associated with LGMD2A) accounted for the greatest number of cases, seen in 72 (17%) of the 435 patients.

Thanks to the ongoing success of the MYO-SEQ project, the rare disease research community is benefitting from an ever-improving understanding of neuromuscular diseases. We continue to contribute to the diagnostic pathway of patients affected by limb-girdle muscular dystrophy, while also improving awareness of these rare diseases and facilitating the integration of NGS technologies into healthcare.

TO LEARN MORE ABOUT THE MYO-SEQ PROJECT VISIT MYO-SEQ.ORG