'The Magic Lab': Using genomics to work miracles for patients with rare diseases

Ufrieda Ho

Prof Shahida Moosa and her patient Anothando Kabingesi in front of the new home Moosa helped secure for this rare disease sufferer and her family. Photo by Newton Stanford

The Rare Disease Genomics research group at Stellenbosch University (SU), the first of its kind in sub-Saharan Africa, is at the cutting edge of genetic medicine and large-scale genomic sequencing research. The group searches for answers to deepen the value of science, and to make the unknown a little bit less scary.

Late one July night in 2022, head of the group Prof Shahida Moosa received a desperate message from the mother of one of her patients.

The photos that were attached to the message showed the rat-chewed fingers of four-year-old Anothando Kabingesi. The toddler suffers from a rare condition, called 'Joubert syndrome', a disorder that affects brain development and hampers balance, coordination, breathing, eye movement and muscle tone.

Given her condition, Anothando wasn’t able to swat away the rats or cry out easily to her mother, Nonhlanhla Kabingesi.

At the time, Kabingesi and her four children, on a housing waiting list for six years already, were living in a shack in Mfuleni. The toddler’s missed milestones had been pushed back even further because of her living conditions.

Moosa first met Anothando at Tygerberg Hospital, where Moosa is also the head of Medical Genetics and the Undiagnosed Disease Programme. At that point, Anothando was just a few months old and no one had yet been able to pinpoint her condition.

Based on Anothando’s clinical features and on imaging analysis, Moosa had a differential diagnosis in mind. In order to definitively diagnose Anothando, Moosa referred her for genetic testing. (Tygerberg Hospital is currently the only public healthcare facility in the country to offer such testing.)

“I was praying to meet a kind doctor and then I found Prof Moosa,” Kabingesi says.

Photo by Newton Stanford

Types of genetic testing

Genetic testing looks for changes, or or so-called 'mutations' or 'variants', in DNA – the unique ‘instruction book’ that makes up each individual human being.

Genetic testing can take various forms: Single-gene testing is used when a doctor wants to confirm a specific condition or syndrome, multigene panel testing focuses on specific categories of medical conditions being investigated, and large-scale genetic testing constitutes exome and genome sequencing.

The difference between these two types of sequencing lies in the range of DNA coverage of the two tests used. During whole exome sequencing (WES), the tests look at those parts of the genome that contain the DNA code for making proteins. In the case of whole genome sequencing (WGS), all of the genome – both its coding and non-coding regions – is mapped.

Large-scale genetic testing has become a powerful weapon for understanding the genomics of rare diseases. It is this type of testing that was conducted on Anothando.

Better the devil you know

The results indicated that Anothando, Kabingesi's youngest child, suffers from Joubert syndrome. Suddenly, having a name for the condition, everything seemed less of a terrifying mystery to Kabingesi.

“I used to be crying alone, but I knew I was going to put this name – Joubert syndrome – into my phone and I was going to find out more for my Ano,” she says.

She adds that, prior to receiving the test results, she blamed herself for Anothando’s situation.

“I had been asking myself all that time if I did something wrong when I was pregnant; maybe I ate something bad or it was because I didn’t remove my [contraceptive] patch till two months after I found out I was pregnant. But Prof Moosa was very calm with me and told me not to worry. She listened to me even though English is not my tongue; she heard what was in my mind and in my heart – she always meets me half of the way,” says Kabingesi.

Being able to name a rare condition is a huge step forward for the families of patients, says Moosa. Next, matching the known characteristics of a condition with the patient’s individual situation means a course of treatment, intervention and support can start to take shape.

In Anothando’s case, support involved Moosa developing a long-term patient-doctor relationship with the family. Moosa intentionally goes beyond the reach of science and medicine, understanding that human connection too is a cornerstone of well-being, especially in the case of children, her key focus.

After seeing the horrific pictures of Ano’s hands, Moosa was able to motivate the fast-tracking of the housing application for Ano, as a special needs child, and her family. Kabingesi says: “I don’t know what Prof Moosa did, but in the next few days, I got a call from the housing people and they said I must come fetch my keys for my house in Eerste River. And now my Anothando is much better.”

No money, no data

For Moosa, the true value of science lies in closing the gap between, on the one hand, cutting-edge research and technological advances, and on the other hand, its application, thereby protecting the most vulnerable patients.

“Our first problem, however, is funding,” she says. “We have the technology and the machines that do the sequencing right here in the state-of-the-art Biomedical Research Institute at SU, and we don’t have a shortage of people coming forward, wanting to have testing done. But I only have enough money to do tests on maybe half of the people that I would like to test at the moment.” (WES testing costs between R7 000 and R10 000 per patient.)

Moosa's research is currently being funded by the Early Investigators’ Programme of the South African Medical Research Council. The aim, she says, is to have more people tested and diagnosed, and to create a larger database that can constantly grow to widen the scope of understanding of rare conditions. This is a dire necessity in Africa – even as the cradle of humankind, host to the greatest genetic diversity on Earth, the region is under-researched.

“Most genetic research and testing is not being done in Africa. This means that when I read the exome of one child or the genome of another and I find some ‘spelling error’ [a variant in the ways the genes have been sequenced], I often don’t know how to interpret it. Is it something that is present in healthy African people or is it something to worry about? We don’t know because the variation is simply not represented in the limited databases that we have.”

Moosa says it puts the continent on the back foot and at a greater risk of falling behind as genetic medicine reshapes the future of healthcare by offering targeted and tailored medical care for individuals. She adds that it will also be a missed opportunity for the continent if it fails to, early on, invest in and adopt technology that will cut healthcare costs in the long run.

Photo by Damian Schumann

The case for mainstreaming genetic testing

From the examples Moosa offers, it is clear that the impact of genetic medicine is far-reaching. It can take patients with an undiagnosed condition off the merry-go-round of doctor visits and testing-related hospitalisation. It can eliminate the trial-and-error treatment of conditions by matching someone’s genetic profile with a targeted drug regime. It enables the accurate assessment of a patient’s risk, the prescription of the correct preventative measures, and timely intervention to stave off the onset of severe illnesses like cancer. It even improves a doctor’s prediction of how a particular patient about to undergo surgery will tolerate different anaesthetic drugs.

But medical health insurance companies and authorities need to wake up to this shifting landscape of medical treatment, Moosa urges. Alongside the lack of funding, this is the second major hurdle to bringing genetic medicine to the mainstream.

“Ultimately, it doesn’t matter which area of medicine you’re looking at, incorporating genetics brings down costs. We are realising more and more that genetics should actually feature higher up in differential diagnosis. We need to be able to get this across to the Department of Health and to medical aids – it serves their purposes as well as that of our patients.”

More geneticists, please

There’s also a third barrier to making genetic medicine more routine: the dearth of medical geneticists, genetic counsellors, laboratory geneticists and bioinformaticians in the country, and of universities that offer training in this field.

This deficit renders the Rare Disease Genomics research group a rare beast. Says Moosa: “We need very advanced computer clusters to handle the amount of data that comes out of our sequencing machines and once this happens, we need a very skilled person or group of people to analyse and interpret the data. So, the bottleneck is not the long time (of up to six months) that it takes to get a test result; it’s finding enough skilled people to interpret the data. Currently, there are only about 12 medical geneticists in the country. This workforce is not nearly enough to meet the needs of the population of undiagnosed families searching for answers.”

Addressing this problem starts with improving genetic literacy among doctors, nurses and the general public, Moosa believes. Being able to better identify candidates for genetic testing means fewer patients fall through the cracks, left to believe there is no hope for them.

Showcasing the potential of genetic medicine is one way to raise awareness of this developing field. In turn, this awareness can attract more professionals to careers in genetic medicine and in its sub-disciplines.

Molecular biology honours student Jess Cormick is one of the newcomers to the field, majoring in human genetics. She tells how she was first introduced to the Rare Disease Genomics research group and its genetics lab in the Biomedical Research Institute, nicknamed ‘The Magic Lab’.

Whilst going for interviews to narrow down her choices of a unit at which to complete her honours research requirements, she came across Moosa’s unit. Upon her arrival there, she saw bright colours, balloons and fluffy toys everywhere, she remembers.

“I was just thinking, ‘What is this place?’ when the professor explained that they were about to have a rare diseases day in the hospital and were taking these ‘rare bears’ – fluffy toys made especially for children with rare diseases – to the paediatrics unit.

“I could hear the professor’s passion; she’s all about the people behind the diagnoses. She always asks things like, ‘Is this child going to be safe at home with the diagnosis?’ or, ‘Where can we put them in school?’ And that’s what drew me to the unit. I never went into science for the data, I went into science to help, in my small way, the people behind the data,” she says.

This attitude and purpose make Cormick a star science communicator, especially when schoolchildren visit the unit. She explains: “Recently, we had some grade 11s visit us and I explained to them that I am not a doctor, so I don’t give medicine to patients. I’m more like Sherlock Holmes, a detective looking for answers, finding out what the problem is.”

Cormick’s work involves channelling data through a bioinformatics pipeline, using different codes and thresholds to set filters for the data and, at each step, honing in further on the parts in the sequencing that point to a rare disease.

“We would filter, for example, for pathogenic variants, rare variants and other filters that come from existing databases,” she says.

The value of an answer

Cormick contributes her findings to genetic data libraries and, ultimately, the field’s global knowledge base so that other researchers and clinicians can lean on the documented information in their quest for answers.

And when it comes to illness, an answer matters. Some people wait 15 or more years for a diagnosis – this is why Cormick believes genetic testing must become accessible as a part of mainstream public health services.

For her, the true value of science becomes clear when she sees the young patients in the paediatrics ward simply being kids and their caregivers confident in knowing that they are not alone. “I couldn’t imagine doing anything else,” she says.

In Kabingesi’s words: “As a mother, you sometimes know that something is wrong, but you don’t want to go to the clinic because you are scared. But I want to say to others, ‘It’s better to know than not to know because it’s only then that your child can be helped.’

“There are people who don’t trust, but I ask God to give me strength and I trust the doctors because I can see that Anothando is walking now in this new house because she can hold onto the walls. It’s like Prof Moosa says, I can see miracles with this child.”

According to the World Health Organization, around 400 million people worldwide are affected by rare diseases. In South Africa, the estimate is 1 in every 15 people, says the non-profit organisation Rare Diseases SA. This means just over 4 million South Africans are living with a condition that affects a minority of people within the general population.

In 2018, Dr Tedros Adhanom Ghebreyesus, the director-general of the WHO, framed the support of people with rare diseases as a part of meeting the United Nations’ Sustainable Development Goals: “The vision of the Sustainable Development Goals is a world in which no one is left behind, including people who suffer from rare diseases. Just because a disease affects a small number of people does not make it irrelevant or less important”

In South Africa, there are about 7 000 known rare diseases, children being the worst affected. According to Rare Diseases SA, about 70% of rare diseases arise from genetic factors and are considered congenital disorders. For many people, their condition is not identified at birth but manifests later on in life only.

Rare disease sufferers need better support if they are to live rich, fulfilling lives. This support, Rare Diseases SA believes, should extend to ensuring access to better diagnostics and a wide-ranging package of care, and to improving research.