“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 his condition were discovered around the world, negative (in other words, normal) genetic test results were reported back to us 13 times.
It seems strange, but each normal test result was extremely disappointing. It meant that we didn’t yet have an answer and that we would need to test another gene, hoping those results one would come back with an explanation for my son’s rare muscle disorder.
At the time, each genetic test examined just one gene, through a process called Sanger sequencing. Every test required a painful blood draw, insurance authorization, and an agonizing four- to six-week wait to hear whether we had discovered the genetic cause of my son’s disorder.
But there’s good news: With new genetic testing technology, we can now test entire panels of genes at one time. Repeated, long wait times like those that we experienced will soon be a thing of the past.
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 abnormally located in the middle of the muscle cell, rather than near the edges. Symptoms include skeletal muscle weakness and, often, breathing difficulties. In my son’s case, CNM has led to the need for a nighttime ventilator, severe scoliosis, feeding challenges, and fatigue. AJ 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, unexplained 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. Are there critical treatments available that are being missed right now? Could future children or members of the extended family be affected? Are there others 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. Alan Beggs, PhD, our well-trusted muscle researcher at the hospital, presented the opportunity, which involved whole genome sequencing for AJ, my husband, and me. Researchers then analyzed the data and looked for a variant that might be consistent across all three of us.
After 11 years without an answer, we finally 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. We were then able to pursue clinical confirmation of these findings from a clinical genetic testing center. The feeling of relief was tremendous, even joyous. We had an answer! The phantom disrupting AJ’s health had been revealed.
Titin is aptly named: it is the largest known protein in the human body. Weighing in at 3.8 million daltons, spanning 363 exons at a length greater than one micrometer, it is the heavyweight champion of human proteins. It is estimated that the average person carries as much as one pound of this protein. Its enormous size made it unwieldy to sequence using the older Sanger sequencing methods, so AJ’s genetic variant had eluded discovery until new 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. These relatives have now started drug treatment for DCM or are having more careful monitoring of their cardiac status, as will AJ.
Finally knowing the genetic cause helps me to understand many aspects of my son’s condition and has inspired me to tame this ghost by further supporting research on CNM’s mechanisms and potential future treatments. I have a greater understanding of the medical conditions that AJ and our relatives are at risk for and can cross off conditions that they are 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. We started a public Titin Facebook group to share research, and I encourage affected families to participate in the CMDIR, an online global registry for congenital muscle disease. I hope that with the creation of more genetic testing panels in the area of neuromuscular disease, the diagnostic journey for other families will be much shorter than ours.