“Negative.” “Normal.” “Fails to confirm the diagnosis of . . .” “Etiology of the patient’s disease phenotype remains unknown.”
These are words I heard repeatedly in the first 11 years of my son’s life. Even as new genes for my son’s rare muscle disorder were discovered around the world, negative or “normal” genetic test results were reported back to us 13 times.
It seems strange, but a “normal” test result was extremely disappointing. Each test required a painful blood draw, insurance authorization and an agonizing four- to six-week period of waiting.
My son, AJ, was diagnosed in infancy with centronuclear myopathy (CNM) by muscle biopsy. CNM is a class of inherited muscle disorders where the nuclei are located in the middle of the muscle cell, rather than near the edges. Symptoms include skeletal muscle weakness and, often, breathing difficulties. My son needs a nighttime ventilator and has severe scoliosis, feeding challenges and fatigue. He can walk only short distances and needs a wheelchair or power scooter for longer distances.
Step by step, I became an expert in a disease I had never heard of, serving as a personal medical case manager, physical therapist and genetics expert. I learned new skills — negotiating medical bills, scheduling appointments, ordering medical equipment, working a ventilator — and made plenty of mistakes along the way. I learned to be an advocate, for my son and eventually for others with myopathies.
But I also wanted a genetic answer for my son. During tough times when AJ was sick or plagued by long periods of fatigue, I wondered: What is this ghost that haunts his body, disrupting our daily life? What is the mechanism of his disease? I would try to picture AJ’s muscle cells and wonder what was going on in them. I even wondered if the doctor had accidentally switched AJ’s biopsy results. There was nothing tangible to grasp onto.
I also wondered about AJ’s medical future. Were there critical treatments available that were being missed? Could future children or members of our extended family be affected? Were there people out there with the same genetic variant from whom we could learn?
Hoping to find answers, we participated in a research challenge led by Boston Children’s Hospital, known as the CLARITY Challenge. Alan Beggs, PhD, our trusted muscle researcher at the hospital’s Manton Center for Orphan Disease Research, presented the opportunity. AJ, my husband and I would undergo whole-genome sequencing. Researchers would then analyze the data and look for a variant that might be consistent across all three of us. Ours was one of three families to participate.
The CLARITY Challenge goal was to identify best methods and practices for clinical genomics and provide meaningful results to patients and their families. But a side result — the possibility that excited us — could be discovery of the variant causing AJ’s myopathy.
As part of an extensive consenting process, we were counseled about what the risks were and what results would and wouldn’t be reported back to us. My son, age 10 at the time, had to explain his understanding of the research in his own words to give his assent. He did a fantastic job and I was really proud of him. He was well prepared to ace his seventh grade genetics class!
The researchers probed me to see if I had privacy concerns. Loss of privacy came nowhere near my biggest fear: that even worldwide teams of experts, utilizing the latest technology, would be unable to find an answer.
One year and four months after our blood was collected, we heard that results were ready to share with our doctors. We would hear the results in a phone call several weeks away. The anticipation and waiting were agonizing! We had been down this road so many times before.
To alleviate the anxiety, I created a countdown on our fireplace mantle: a set of numbered sticky-notes. As the date of our results neared, we pulled the notes down one by one. One day I pulled a note, one day AJ pulled a note, one day his father pulled a note, one day each of AJ’s grandmothers pulled a note.
AJ told my mom: “The answer doesn’t matter that much to me, but it’s making my mom crazy! So, for that reason, I hope they find an answer!”
A giant among proteins
Finally, after 11 years of waiting, we learned that the researchers had identified the likely genetic cause of AJ’s muscle disorder. The involved gene is called TTN, which codes for a protein inside muscle cells called Titin that is crucial for proper muscle function. AJ has variants in both his copies of TTN.
The feeling of relief was tremendous, even joyous. We had an answer! The phantom disrupting AJ’s health was now revealed. We had a celebration dinner with family featuring a Titin cake.
Titin is the largest known protein in the human body, a heavyweight champion weighing in at 3.8 million Daltons, spanning 363 exons and more than one micrometer in length. It is estimated that the average person carries as much as one pound of this protein, a key part of the contractile apparatus in muscle cells.
Its enormous size made the TTN gene too unwieldy to sequence using the older Sanger sequencing methods, so AJ’s genetic variant had eluded discovery until whole-genome sequencing technology revealed it.
In subsequent months, we were able to have extended family members tested. This led to an unexpected twist. Several of AJ’s aunts, cousins and an uncle tested positive for single allele variants in TTN, which are known to be associated with a heart problem known as dilated cardiomyopathy (DCM). Further clinical examination revealed mild DCM in three of AJ’s relatives with the TTN variant — and in me. All of us have now started drug treatment for DCM. AJ has no symptoms, at least for now, but is having his cardiac status carefully monitored.
Finally having this answer helps me to understand many aspects of my son’s condition and has inspired me to further support of research on CNM’s mechanisms and potential future treatments to tame this ghost. I 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 journey, but it is a hugely important milestone along the way. I hope that our discovery will benefit all people with CNM caused by this variant. We’ve started a public Titin Facebook group to share research, and I encourage affected families to participate in CMDIR, an online global registry for congenital muscle disease.