The evening before he died, Hogan Teem stayed in. It was December 12, 2012, and the teenager played cards with his mother at their home in Clayton, North Carolina. His girlfriend spent Wednesdays with her family, and card games had become a weekly tradition. This time they settled down to a session of Phase 10. Hogan beat his mother, closing the gap in their running score, now at 13 matches to 11. Around 9.30pm, he went to bed; the following day was a busy day of high school, ending with baseball practice. There was no indication that it would be his last.
Hogan was physically fit, spending long summer days mowing lawns in the North Carolina heat. He played American football, basketball, baseball and golf. He loved swimming, hiking and fishing. He went on mission trips with his church. He never suffered illness or missed a day of school. To all intents and purposes, he was a perfectly healthy 17-year-old.
Baseball practice on December 13 had been business as usual. Participating in light conditioning work, Hogan took it easy so as not to put strain on his ankle, which he had sprained a couple of weeks earlier. Then, midway through practice, he approached one of his coaches, saying: “Coach, I don’t feel right.” Before the coach could respond, Hogan blacked out and fell to the ground. The coaches administered CPR. An ambulance arrived almost instantly, and paramedics discerned a faint heartbeat. Hogan’s parents, Allyson and David Teem, arrived at the school, and Allyson travelled in the ambulance. On the way to the hospital, paramedics lost Hogan’s heartbeat. After several minutes of frantic work at the roadside they recovered it and sped on towards the emergency room.
In an effort to keep her son awake, Allyson taunted him about the card game. “I was yelling, ‘You cheated! You owe me a card game,’” she says. “Then I said, ‘OK, you won fair and square, but it’s still 13-11!’” Despite Allyson’s efforts to rouse her son, Hogan was unresponsive by the time they arrived at the hospital. Medical staff worked on him but, after 45 minutes, admitted there was nothing more they could do.
Hogan had suffered an acute cardiac event, brought on by a rare and previously undiagnosed genetic condition known as an arrhythmogenic right ventricular cardiomyopathy, or ARVC. There had been no reason to suspect that Hogan was at risk, and doctors don’t commonly run tests for ARVC. The tragedy was unforeseeable.
Hogan had been adopted when he was five weeks old. Seventeen years later, his biological parents were raising three children of their own – two sons and a daughter, all full siblings to Hogan. Allyson regularly sent the family letters and pictures of Hogan, but they had no direct contact; the protocol was to send documents via the adoption agency. After Hogan’s death, Allyson realised that the siblings could well carry the same genetic disorder and wrote to his biological parents, urging them to get the family checked.
Due to bureaucratic procedures, it took nine months to get the message through. The two boys, their sister and parents underwent cardiac imaging to look for signs of ARVC. The results came back normal, and the family breathed a collective sigh of relief.
Then, four years later, the youngest sibling, Ethan White – then 14 – complained of chest pains while playing basketball at church. He called his mother, who arrived to find him grey and clammy, complaining of pain in his jaw and arm – symptoms of a heart attack. His mother rushed him to hospital where his heart rate was discovered to be 263 beats per minute. The medical staff thought there was an error with the reading – the average heart rate fluctuates between 60-100bpm. Ethan’s condition worsened. Doctors tried medications but none could be found that alleviated his condition. Just as medical staff were preparing to defibrillate him, Ethan vomited and his heart rate lowered.
His condition stabilised, and Ethan was transferred to Duke University Hospital, the major medical centre in that part of North Carolina, where he was monitored and fitted with an inbuilt defibrillator. It was clear to staff that Ethan had also experienced an acute cardiac event consistent with ARVC and that another attack was likely. The defibrillator was designed to restart his heart in the event of another attack. An MRI scan of his brother, Austin, confirmed he also had ARVC. The two brothers had inherited the same genetic problem as Hogan, despite all the tests finding nothing to indicate a genetic cause. Yet how else could three brothers raised in different families, in different parts of the state, develop the same condition?
With local medical staff stumped, and no further avenues of investigation available, Ethan and Austin were referred to the Undiagnosed Diseases Network (UDN), a group of 12 clinical research hubs designed to delve into chronic illnesses that have previously been undiagnosed, misdiagnosed or simply written off as psychosomatic. Bringing together experts in neurology, immunology, cardiology, endocrinology, genetics, rheumatology and more, the UDN had been custom-built to delve into just such a medical mystery.
In July, in North Carolina, the tree-lined avenues of Duke University are a furnace of mid-summer heat. The university is part of the famed “Research Triangle”, a multi-county area linking Duke with North Carolina State University and the University of North Carolina at Chapel Hill. Duke University, based in Durham, boasts a formidable campus, with more than 100 buildings, 1,600 medical students, 2,400 clinical staff – and Dr Vandana Shashi, principal investigator for the Duke UDN site.
Shashi, 60, speaks with a calm and benevolent authority. She has worked at Duke for around ten years. “I’m a clinical geneticist and a paediatrician, so I have seen patients who were difficult to diagnose my entire life,” she says.
In 2011, Shashi found herself discussing the difficulty of diagnosing genetic diseases with a colleague, Dr David Goldstein. At that time, just 50 per cent of patients with genetic diseases received a diagnosis. Together, they started working with new gene-sequencing technology, and in 2012 they published work demonstrating the efficacy of this tool in helping to reach a diagnosis.
Two years later, Shashi heard that the National Institutes of Health – a research centre affiliated with the US Department of Health – was looking to expand a small programme aimed at helping the most difficult to diagnose patients, and set up research centres at clinical sites across the country. Shashi immediately applied, and Duke was accepted in 2014 as one of the first clinical sites alongside UCLA, Stanford, Vanderbilt, Baylor and a co-ordinating centre based at Harvard. This was the first iteration of the UDN.
The Duke site took on its first patients in 2015. To date, it has accepted 199 applicants and made 79 diagnoses. As of 2019, the UDN as a whole has received 3,601 patient applications, 1,372 of which it has been able to accept. It has reached a diagnosis in 323 cases.
“The mission of the UDN was and is to provide diagnostic services to patients who have had difficulty getting a diagnosis, and also to be able to have the patients participate in research activities,” Shashi explains.
In the US, a rare disease is defined as something that affects fewer than 200,000 people, and an ultra-rare disease as affecting fewer than 2,000 people. By their very nature they are hard to diagnose, simply because so few patients are available to study, and are often misdiagnosed. Without any reason to suspect otherwise, doctors have to rely on what they know. In many cases, like that of Ethan and Austin, they know what the problem is but fail to unearth genetic evidence for it – a vital component in identifying at-risk family members and formulating a treatment plan. Frustrated by months or years of disjointed medical testing, a doctor may suggest patients apply to the UDN in a final bid for answers.
The Duke team reviews applications in a meeting every Tuesday. In order for a patient to be eligible, they must have an “objective finding” – a first clue or loose thread for the team to begin unravelling. “There is a perception that ‘undiagnosed’ also means ‘functional’, so the two can be confused,” explains Shashi. “So if you have symptoms like pain or fatigue, yes you can be undiagnosed, but that doesn’t mean you have a true objective undiagnosed disease. These symptoms could be due to pre-existing functional diseases.”
A functional disease is one that exhibits symptoms – nausea, say, or light-headedness – and affects functionality. Because such symptoms are common, they are often easy to diagnose as caused by common illnesses. A UDN patient may display these symptoms, but it is the objective finding – the first unusual clue – that makes them suitable.
Once a patient has been accepted, representatives from each of the UDN sites join a call to share suggestions regarding possible diagnoses or tests. This culture of collaboration means specialists can confer in real time, working together to find a diagnosis. The network has the resources to examine a patient’s history in detail and formulate a working hypothesis based on this data, leading to a suite of tests tailored around the specific condition, a large part of which involves closely examining genetic data for rare or unusual variants or changes.
To date, the UDN has discovered and published papers on two new disease genes, NACC1 and IRF2BPL. After identifying these genes in children, they were able to track down other patients affected by the same diseases. They have also diagnosed a patient with a variant in the KCNC1 gene, known to cause progressive myoclonic epilepsy. Due to that diagnosis, the patient is now enrolling in a clinical trial at another institution that could lead to a drug trial specific to her gene variant.
The majority of UDN patients come from the United States, but international patients are accepted as long as they can afford to travel. Patients apply with suspected auto-immune diseases, infectious diseases, rheumatological diseases, genetic diseases and neurological diseases – although it is not often clear which category they fit into when they first visit the UDN.
Typically, the UDN has a diagnosis rate of 30 per cent, with the Duke site slightly higher at 40 per cent. Due to the rarity of many of the conditions, this percentage represents a significant accomplishment. The reality, however, is that most patients will not receive a diagnosis. “Most patients tell us they expect not to get an answer, because they’ve already been through so many tests elsewhere,” says Shashi. “They come in with the idea that this is their last hope, and they’ll be surprised if they get an answer.”
Holly, 47, is still waiting. Five years ago, she began experiencing pain in the bottom of her feet, which spread to her legs and quads. At first she saw an orthopaedist, then a rheumatologist, and eventually a neurologist, who performed tests that suggested a muscle disease but didn’t result in a specific diagnosis. The neurologist suggested she would be a good candidate for the UDN, and she underwent her first round of UDN tests in summer 2018.
“I was very hopeful when I got in touch with the UDN,” Holly says. “I was excited to have someone take a deeper look, to try to make sure they encompass everything they felt might be to blame, and to have so many different specialists looking at different angles.”
But full genome sequencing, blood work and a skin biopsy revealed no new information. A year later, Holly is no closer to understanding her condition. “It’s hard to put into words the frustration at this point,” she says. “It’s very disappointing to continue to seek out answers and not be able to find a shred of what’s causing this – just something to provide relief and help me with quality of life.”
Shashi says that the team is realistic with patients. “We tell them their chances are not great,” she says. “It’s very stimulating and rewarding when you do find an answer. But, for us, that’s what drives us, to try to solve these most difficult situations.”
A common refrain among patients applying for the UDN is that they “want their old life back.” Whatever their condition, chances are it has robbed them of their health, their mobility, the chance to play with their children, the chance to follow the career they wanted.
Jackie Boyd, 27, is one such patient. Around 2013, she began experiencing numbness in her hands which rapidly spread to other parts of her body. “It felt like sitting on your hands and them being numb,” she says. “I thought ‘maybe I slept wrong’ but it lasted for weeks, then months.” Boyd rapidly developed ataxia, a loss of muscle control and balance. Her doctor prescribed pills which didn’t seem to work. She then saw a neurologist who essentially told her there was nothing wrong with her.
The same year, she began a new job as a correctional officer. One day, a colleague noticed her struggling to move upstairs to check on prisoners, and eventually she was relocated to a smaller, single-storey facility and given a position in administration. The job change was a blow, but what bothers her most is finding it hard to play with her eight year-old son. Although Boyd is able to walk with difficulty, she typically uses a wheelchair.
“My son is sometimes sad,” she says. “I can’t push him to do things now, I get up to play sports with him and I’m tired. It’s hard. He worries about me more than I wish he had to. If he hears me fall down at home he calls, ‘Are you OK mom? Did you fall down?’ I tell him I’m OK. Sometimes I’m not, but I’m fine enough. I don’t want him to worry about me, it’s not his job.”
Boyd was referred to the UDN in April 2019. At first the team thought she had genetic ataxia, a condition associated with progressive loss of coordination. However, neurologist Dr Vern Juel noticed symptoms consistent with a rheumatological disease called Sjogren’s syndrome, which led to an antibody test.
“She had one of the antibodies associated with Sjogren’s disease, but she didn’t have the full repertoire of what one would expect with Sjogren’s,” Juel explains. Sjogren’s can present with extreme fatigue, joint swelling and stiffness – symptoms which matched Boyd’s condition. The anomaly was that Boyd did not display the dry eyes or mouth more commonly associated with the condition.
“One of the great things about this being a UDN case is if I had seen the patient on my own, the first thing I would have wanted her to do would be to see a neurologist, and that could take another month or two,” says rheumatologist Dr Rebecca Sadun, who also worked on Boyd’s case. “I think this collaboration is crucial; I actually read over the notes of an external rheumatologist who also thought this was a likely case of Sjogren’s but didn’t have the advantage of being able to talk to a neurologist, so was mostly focusing on the patient’s joint symptoms as a solo issue, and not as part of a larger disease.”
While initial testing pointed in the direction of Sjogren’s, Boyd needed to return to Duke for additional testing to confirm the diagnosis. On July 9, she is back for a lip biopsy, designed to look for evidence of inflammation of the salivary glands, a hallmark of Sjogren’s.
“Sometimes, when people are told there’s nothing wrong with them they just accept it, stay home and get worse,” Boyd says from the examining chair while she waits for a numbing cream to take effect on her lip. “It’s been six years and my body has been getting worse. You think ‘what if it’s this, or what if it’s that?’ I don’t have anything to lose by coming [to the UDN]. At this point, I still want to know what this is, I want to know how long I have left to do certain things independently. I want to be able to make some kind of plan for my son.”
As the numbing cream takes effect, the doctor returns and removes an inch-long sliver of tissue from the inside of Boyd’s lower lip before stitching her up. Tomorrow she is scheduled for a lumbar puncture in order to test her cerebrospinal fluid. It is a notoriously painful procedure, but should be Boyd’s last at the UDN.
“She’s a work in progress at this point,” says Sadun. “But we have a working theory and we’re hopeful that [after these tests] we can make that diagnosis and get her started on therapy.”
Auto-immune diseases are common at the UDN, but by far the majority of work at the Duke site – 85 per cent – is on diseases with a suspected genetic cause. Following Ethan White’s cardiac event, he and his brother were accepted to the UDN in September 2017. In their week of tests, the brothers saw experts in genetics, cardiology, ophthalmology and neuropsychology. Because he suffers from type one diabetes, Ethan also saw an endocrinologist, although no link was found. To ensure a comprehensive analysis, the UDN even reached out to the Teem family for a sample of Hogan’s DNA, which the coroner was able to provide.
The team then sequenced the brothers’ exome – the part of the genome that makes up just 1-2 per cent of our genetic data but is the part most rich in mutations that have an effect on disease. Exome sequencing is not unique to the UDN; in fact, 75 per cent of UDN patients at the Duke site have previously had their exome analysed, but their doctors have been unable to find any clues in the results. As current estimates suggest 80 per cent of disease mutations can be found within the exome, however, the UDN decided to start its investigation there.
“Our site has a very agnostic approach to the genome,” says Shashi. “We not only look at the genes which we think might be causing the problem, but all the other genes as well, picking out variants which we think are compelling. That has led us to pick out candidate genes that otherwise might be missed in a clinical laboratory.”
ARVC is caused by changes in one of a number of genes that produce proteins necessary for proper function of the heart. These genetic changes lead to an abnormal or missing protein, causing a breakdown of the muscle tissue and a build-up of fatty deposits. This, in turn, significantly inhibits the heart’s ability to function normally. Genetic changes within 13 genes are currently known to cause ARVC, yet around 50 per cent of patients will come up negative when tested for them, indicating the existence of additional, as-yet-undiscovered genes associated with ARVC.
In analysing the brothers’ exome, the UDN uncovered something unique: variants in a novel gene which they were unable to locate in medical databases compiling genetic data from over 200,000 people who do not have rare diseases. “Typically when a genetic variant is very rare, we think there’s a chance it could be disease-causing,” says Heidi Cope, the lead genetic counsellor on the case. “If we saw the variant in 3,000 people, most likely it’s benign, as you [otherwise] wouldn’t see it that often in that many healthy people.”
With this gene a likely candidate, the next step was to study it in different models in order to monitor how the gene is expressed and run tests without having to study Ethan and Austin’s hearts directly. Dr Andrew Landstrom, a paediatric cardiologist working out of a complex of labyrinthine laboratories at Duke University, agreed to lend his expertise on the case.
The main tool in Landstrom’s arsenal is induced pluripotent stem cells. In this process, blood cells are taken from an affected patient and, using molecular genetics, are encouraged to release all of their differentiation, reverting back to the stem cell state. This essentially forms a blank slate containing all of a patient’s genetic information. By exposing these stem cells to certain chemical signals, researchers are able to steer them towards becoming whichever type of cell is most pertinent to their research, from liver cells to lung cells.
In this case, Landstrom’s team re-programmed stem cells from the brothers to become heart cells, from which they were able to grow heart tissue. “These stem cells carry all the same genetic markers as the patient so we can use it as a tool, like having their hearts right in front of us without ever going near them,” Landstrom says. He produces a tray of heart cells from an incubator and places them under a microscope. Swirls of heart tissue pulse on the screen, the effect something like a living version of Van Gogh’s The Starry Night.
Researchers first look for evidence that the gene they have identified causes the cell to function as hypothesised. Because defective genes produce abnormal proteins, a cell made up of these genes will function abnormally. In this case, Austin, Ethan and Hogan’s hearts displayed a high build-up of fatty tissue. If the in-vitro cells also develop this, it will be a strong indication that the gene identified by Cope and her team is the culprit. The team will also monitor the in-vitro cells to see if they develop the same arrhythmias displayed by the brothers.
Frequently, as in this case, the UDN also works with its Model Organism Screening Center laboratories to model genes in zebrafish models. Professor Monte Westerfield, at the University of Oregon, runs this programme. His team use CRISPR Cas9 gene-editing tools to generate a zebrafish embryo with the correct mutation. Because there is a high degree of genetic conservation among vertebrates, zebrafish allow researchers to make an almost exact genetic replica of human genes.
“Zebrafish are transparent during early developmental stages which means within a few days you can actually see the heart beating,” Westerfield says. “We can then monitor its heart rate for arrhythmia or circulatory issues, and are also planning to do some high-resolution imaging to understand the cellular nature of the disease.” Westerfield expects the experiments will yield results within two months, but it is already clear the gene is expressed in the heart. This, he says, is “pretty good evidence that it is in the right place.”
Should the animal trials prove fruitful, Landstrom is confident that the UDN will be able to provide a genetic diagnosis. For the first time, the Teems and the Whites will be able to put a name to the cause of their suffering. Considering so few patients ever get this far, Landstrom describes this as a “huge step.”
The UDN hopes to publish its research on this gene in early 2020; until then, the name of the specific gene is confidential. Cope explains that, once the UDN publishes its research, the gene can be added to the panel of ARVC tests, so that future patients can be successfully diagnosed before it is too late. “There are probably lots of families out there that have the gene but wouldn’t know,” she says. “At present, it isn’t public knowledge so a cardiologist wouldn’t know to look for it.”
The goal then will be to develop a medicine that can help regulate the condition and inform treatment for people like Ethan and Austin. Landstrom admits, however, that this type of precision medicine is “a very long term goal that we may never get to in my career.” This means it is unlikely to directly benefit the two brothers.
Although the potential breakthrough will realistically make little immediate difference to his sons’ lives, Jeff White, Austin and Ethan’s father, is thankful for the UDN’s work. “Even if we don’t get anything else out of it, if this means we could help one person – save one life through what we’re doing – that’s good enough for me,” he says.
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