Геномное секвенирование в Окленде спасло жизнь младенцу с редким синдромом, ранее убившему её брата

In a first for New Zealand, genomic sequencing carried out in Auckland led to life-saving treatment for a baby girl with the same rare condition that had killed her brother. Y ou could call Whaiāipo Clarke a one-in-a-million child – but that cliché would be a significant understatement. When her rare autoimmune disorder was discovered a fortnight after her birth in October 2024, she became only the 15th person in the world reported to have been diagnosed with the rare genetic condition called Nocarh syndrome (it’s an easier term to get your head around than what it stands for: neonatal-onset cytopenia, autoinflammation, rash and haemophagocytic lymphohistiocytosis). The global incidence of the disease is about one in a million. Without that prompt diagnosis, Whaiāipo would have died, as her month-old brother Uenuku did in 2017, two years before the condition was first described and recognised. Uenuku was one of twins, but his twin, and a brother born two years later, were unaffected by the condition. Mum Tui Clarke says Whaiāipo’s problems were apparent from the start. She was not breathing properly immediately after being delivered by Caesarean section and was covered in an angry red rash. Clarke thought immediately of the son she had lost. “She looked exactly like him. There were tubes in every part of her body.” Until now, the genetic tests that can diagnose such conditions have all been done overseas – sometimes taking weeks – and the delay can cost lives. This time, however, they were done here, thanks to groundbreaking research at the University of Auckland’s Liggins Institute, which, in late 2023, introduced rapid genomic sequencing for newborns with rare or difficult to diagnose conditions. That effort was funded by philanthropic donors, and three years on, a $5 million gift from a United States-based New Zealander is allowing the diagnostic tests to include children and adults, and an expansion in research to find treatments for currently incurable genetic conditions. Transforming care A dvances in rapid genomic sequencing are transforming neonatal care internationally for critically ill newborns, though New Zealand has been lagging in this area. The Liggins Institute has done rapid genomic sequencing on 60 babies and their parents in the past three years. But a result doesn’t necessarily mean there’s a treatment. In this case, and for the first time, there was. More than 100 babies a year are born here with one of about 7000 rare disorders, of which only a few hundred are treatable. That’s something Liggins director Professor Justin O’Sullivan, who leads the genomic sequencing team, wants to change by developing individualised therapies. Large-scale clinical trials in which the effectiveness of new medicines is usually measured aren’t feasible in these cases, he says, but the data they provide can be helpful. He says some drugs that have failed in trials to provide enough benefit for the bulk of people can be very powerful and useful for small subsets of patients. It’s not that we’re going to fix everybody. But there will be instances where it works and it will have a massive impact. Individualised care is the future of medicine, he says, and it is important that access to quality care isn’t based on the numbers of people who might have a condition. “For those individuals where this is viable, it will make a big impact. That’s what is most exciting. It’s not that we’re going to fix everybody, because that’s not possible. Things will fail and that’s going to be gut wrenching. But there will be instances where it works and it’s going to have a massive impact.” Although only about 40% of rare ­disorders can be diagnosed using gene sequencing, and even fewer can be ­successfully treated, O’Sullivan says the knowledge the tests bring provides parents with some comfort and allows them to consider screening options ahead of future pregnancies. “Actually telling them what they have is one thing, but being able to treat it is a different thing. So what we’re trying to do now is to address that gap by starting to develop new, bespoke treatments.” One of the most promising of these is the use of what are called ASOs (antisense oligonucleotides) that target the messenger RNA produced by a dominant mutated gene. Or, as O’Sullivan describes it, “We just inject them like a drug and it stops the broken message from getting through. It’s a bit like a jamming system when you’re trying to phone somebody.” This intervention was not used on baby Whaiāipo but the institute is now seeking ethical approval to treat two other children with rare genetic disorders diagnosed in recent months by using ASOs made overseas. But O’Sullivan says the treatments can now be made locally, and he hopes this will soon include those of clinical grade. The children are not in hospital but, O’Sullivan says, “they are seriously ill and degenerating and so there is pressure to do this fast.” The Liggins researchers are primarily looking for dominant genetic mutations, meaning only one change in the genome is causing the disease. Another research thrust is to potentially repurpose existing drugs for a different fight, using what’s called a “knowledge graph” to analyse genomic data and protein interactions and identify and rank medications that may be useful for other conditions. He says although the institute currently does the testing and hands the results to clinicians, the aim is for the diagnostics to be done in hospitals in future. “Our hope and our goal is that it goes back into the healthcare system where it belongs.” Pioneer founder T he introduction of rapid genomic sequencing comes more than 50 years after the pioneering work of Professor Sir Graham “Mont” Liggins, after whom the institute is named. In the early 1970s, Liggins showed how antenatal steroid injections could mature the lungs of babies at risk of being born too early. The technique has since been introduced globally, saving tens of thousands of lives. This year is the institute’s 25th anniversary. O’Sullivan never met Liggins, who died in 2010, but says he’d like to think he’d be supportive of the new research. “I hope he would think it has a future – I don’t think the future is just to treat everybody the same.” The institute’s work is a clinical game-changer for doctors at Auckland’s Starship Children’s Hospital faced with previously undiagnosable conditions that have proved fatal for young patients. Tui Clarke and Whaiāipo were flown from Whangārei to the neonatal intensive care unit at Starship three days after her birth, where the mutation was discovered and the diagnosis confirmed by DNA tests. By identifying Whaiāipo’s condition so early, doctors were able to start anti-inflammatory treatment – the inflammation needs to be under control before a bone marrow transplant can be performed to replace the stem cells. It also gave the medics time to find a compatible donor and allow Whaiāipo to grow to a size at which the transplant could be safely performed. The stem cells that saved her came from an Australian donor after a search on the bone marrow donor registry. The transplant was performed in March last year after paediatric rheumatologist Dr Jackie Yan consulted experts in Italy, Switzerland and the United States about treatment options. One of the drugs used to control Whaiāipo’s inflammation had to be imported from Sweden. Bone marrow transplant physician and paediatric oncologist Dr Chia Huan Ng says the earlier diagnosis – the test results were available in 96 hours but could have taken up to six weeks had they been done overseas – undoubtedly improved Whaiāipo’s chances of survival. She might not have been high on the priority list if other parents hadn’t made their children’s information available. It was a huge team effort, she says, with involvement from specialists in rheumatology, immunology, neonatal and paediatric intensive care and others. “Given how unwell she was, and how complicated her case was, the collaboration was really important in her successful outcome.” Ng is still involved in Whaiāipo’s care. “She’s been amazing. She was in ICU for two months and we were all worried she might not survive. When we were able to discharge her in June … that was a big moment.” Tui Clarke and Whaiāipo spent another two months at Ronald McDonald House – which provides accommodation for families with children being treated at Starship – last year before returning home to Rawhiti in the Far North. After completing her most recent checkup last month, Ng described Whaiāipo’s recovery as “remarkable”. “She’s growing, she’s gaining weight, she’s now eating and not requiring any nasogastric feeding.” Follow-up visits every two months to Starship have helped Clarke put to rest traumatic memories of Whaiāipo’s time there as an inpatient. When her daughter first arrived at the intensive care unit, she was put in the same room her son was in when he died. Restoring faith I f Whaiāipo’s survival is something of a medical miracle, for Clarke it was confirmation of the power of her own Christian beliefs – something she had abandoned for a time after Uenuku’s death. “People would say to me, ‘You need to go to church.’ And I’d say to them, ‘No, He gave me a blessing of two and then He took away half.’” Whaiāipo’s treatment journey returned her to her faith. “From the get-go, there were signs and wonders. Coming down here [with Whaiāipo] … being put into the same room where my son died … everywhere there was a rainbow … Uenuku means rainbow.” When Whaiāipo suffered a lung haemorrhage (the first of several) and her condition deteriorated two weeks after the stem cell transplant, doctors told Clarke they were “at capacity for what they could do for her and that she wasn’t improving …” The message was clearly that she should prepare for her daughter’s death. But, Clarke says, that night “the Sky Tower was the colour of a rainbow and I knew her life wouldn’t end the same way. “To unbelievers, this is going to sound insane, but I had a vision of her just as she was, but without all the tubes. And in my vision I saw her with a golden helmet on her head. And I knew straight away it was the armour of God.” Twenty minutes later, she says, Whaiāipo’s condition began to improve. A few months before she turns two, Whaiāipo looks like any other healthy toddler but Clarke says immediately after the transplant, Whaiāipo had “become like a newborn again, with zero strength or muscle tone and unable to focus her eyes”. Her developmental stages have since been delayed by several months – she spoke her first words in January this year when she was 15 months old, and walked for the first time in May. Clarke is immensely grateful that the treatment was available to Whaiāipo, even if it came too late to save Uenuku. His cause of death was recorded as aspirating his mum’s breast milk after his feeding tube dislodged from his stomach, and that’s something she’d like to see changed. “I want it to be recorded that everything that he went through was a result of Nocarh syndrome, so if there is another child ever born in this country that presents like him, the information is readily available. “If it wasn’t for the other parents who have been through something similar, we wouldn’t have had the research to check her. She might not have been high on the priority list if other parents hadn’t made their children’s information available. “What the Liggins Institute does is very, very important. When you go through something like we’ve been through, if it wasn’t for places like this, I wouldn’t have my baby. Our story is truly a testament that faith and medical science can work hand in hand, as long as there’s mutual respect.”