Genetic mystery solved

This story first appeared in the Information Point newsletter Our World in 2012, when Sarah Foye told The Information Point how taking part in the Clarity Challenge at Boston Children’s Hospital solved her sons genetic mystery.  

“Negative.” “Normal.” “Fails to confirm the diagnosis of . . .”. “Etiology of the patient’s disease phenotype remains unknown.” These are all words that we have heard repeatedly in the past 11 years of our son’s life. In fact, negative (normal) genetic test results have been reported back to us 13 times. Each of these tests requires a painful blood draw, insurance authorization and an agonizing 4-6 week period waiting for results. That is a lot of nail biting for us as Mom and Dad.

Our son, AJ, was diagnosed with centronuclear myopathy (CNM) in infancy by muscle biopsy. The biopsy showed some elements of a centronuclear myopathy pattern, but at the time, genetic testing for CNM was limited to the XLMTM (X-linked myotubular myopathy) form, which AJ tested negative for. We have been seeking a genetic confirmation of his disorder since. As researchers worldwide have discovered addition genes responsible for CNM, AJ has been tested for them, but each time the test was negative. The mystery remained. The search continued.

We’ve wondered: what is his definitive diagnosis? What medical conditions is he at risk for? What impact could this have on future children for our extended family and us? What treatments might help our son? The possibility of finding answers to these longstanding questions is one of the many reasons we chose to participate in the CLARITY challenge at Boston Children’s Hospital.

The goal of the CLARITY (Children’s Leadership Award for the Reliable Interpretation and appropriate Transmission of Your genomic information) Challenge was to identify best methods and practices for improving the reliability and accuracy of the genomics-to-clinic pipeline spanning sequencing, analysis, interpretation and reporting – to provide the most meaningful results to patients and their families.

40 academic and commercial organizations applied to participate in the CLARITY Challenge, a contest to identify the putative disease-causing mutations in three young patients. 30 were selected and agreed to compete. 23 submitted entries by the September 30 deadline. Contestants entered from all over the world, including North America, China, India, Israel, Italy, Germany, the Netherlands, Singapore, Slovenia, Spain, Switzerland and Sweden. They had about four months to analyze genomic (DNA) data and medical histories of each of the patients and their families and submit their reports. Boston Children’s Hospital awarded $25,000 in prize money to the winning research teams, which were selected by a six person judging panel.

The contest organizers — Isaac Kohane (director of the hospital’s Informatics Program), David Margulies (executive director of the Gene Partnership at Boston Children’s Hospital) and Alan Beggs (director of the Manton Center for Orphan Disease Research at the hospital) unveiled the winners at the annual conference of the American Society of Human Genetics on November 7.

We are thrilled to share the news that using whole genome and whole exome sequencing, the contestants identified the likely genetic cause of AJ’s muscle disorder. The involved gene is called TTN, which codes for a protein called Titin. Titin is a protein located inside muscle cells, where it is crucial for proper muscle function.

Finally having this answer helps us to understand many aspects of our son’s condition. We now know the gene mutation that is responsible, and we know the protein that it impairs. We know how it was inherited and the risks for other family members. We can begin to understand the problem at the level of the muscle cell and its impact on muscle function. We are inspired to further our efforts in support of CNM research and potential future treatments. We have a greater understanding of the medical conditions that AJ is at risk for and can cross off ones that he is not at risk for. Having a genetic diagnosis is not a final destination on our medical journal, but it is a hugely important milestone along the way. We also hope that this discovery advances the current understanding of CNM overall.

Undoubtedly numerous other families with CNM that have previously eluded genetic diagnosis will turn out to have mutations on the same gene as our family. Thus, a new subcategory of CNM is born: titin myopathy. Titin myopathy now has a place right along other forms of CNM such as XLMTM (X-linked myotubular myopathy), autosomal dominant CNM (Dynamin 2, DNM2), Ryanodine Receptor 1 (RYR1) CNM, and Amphiphysin 2 (BIN1) CNM. Other forms of CNM still remain without a genetic diagnosis and research is ongoing. By learning more about the similarities and differences between the various forms of CNM, hopefully researchers can better understand why these myopathies occur and what treatments may help.

We are truly grateful to have had the opportunity to participate in the CLARITY Challenge. We are happy to have a genetic answer to our family’s questions and hope that subsequent resultant research will help all of our CNM families move further along this journey that we all share. Many thanks to Boston Children’s Hospital and the international contestants for working on our case and working to move the industry of clinical genomics forward.