No Child's Play In Paediatric Precision Medicine

Dr. Jamuar plays an active role in the Singapore Childhood Undiagnosed Disease Programme—Bringing Research Innovations in Diagnosis of Genetic Diseases in Singapore (BRIDGES)—that was set up in 2014 by KKH in collaboration with the Agency for Science, Technology and Research (A*STAR) and Duke-NUS Medical School. It led to the discovery of the ‘Jamuar Syndrome’. Today, Dr. Jamuar helms the role of Overall Lead at BRIDGES.

Dr. Jamuar says, “Before next generation sequencing came about, we could diagnose—maybe—two to four patients a year. With BRIDGES, we are able to diagnose two to four patients a week. This has helped to better manage our patients with suspected genetic diseases. While we are able to identify the aetiology in ~40% of our patients now, there are also others where we see genetic changes that had never been identified in human diseases.

“One such instance was this family that has two young girls with various developmental issues. We couldn’t pin the cause down initially. Eventually, we identified the genetic change that was actually driving their clinical symptoms—and being the first person to have discovered it, the syndrome was named ‘Jamuar Syndrome’. That was significant—not so much because the syndrome is named after me, but that we found an answer for that family.”

Growing Pains in Applying Precision Medicine in Diagnosis

The question remains. If whole exome sequencing and whole genome sequencing can improve the yield of primary diagnostic findings in children with suspected genetic disorders, why are they used as ‘last resort’ tests after a prolonged diagnostic odyssey^[1]?

Dr. Jamuar explains, “Globally, paediatric genetic disorders are classified as rare diseases. But there is increasing realisation that while these diseases may be rare individually, there are over 7,000 of them collectively. These disorders manifest in about 2 to 3% of all newborns, and the prevalence increases to 5 to 6% when they grow up. “One example is familial hypercholesterolemia where very high cholesterol levels are detected in teenage and young adult years. This condition increases the risk of a heart attack. Similarly, the BRCA1 and BRCA2 genes develop into breast and ovarian cancers when one is in their 30s and 40s. These findings are starting to change the conversations Surrounding rare diseases—because we are now understanding their role in common diseases too.”

Dr. Jamuar adds, “And compared to other more known diseases like diabetes, cancers or heart diseases, whenever someone in the family is diagnosed with a rare disease, there is often a lot of guilt attached to it like ‘was it something I did or ate that caused this to happen?’. Other times, patients find it hard to explain their disorders to their families, especially when they can’t put a name to it. “But this is precisely where genetic testing comes in. If we can give a name to the condition, we can know for certain that the condition results from a genetic change that no one has control over. More importantly, that allows us to ask the next question, ‘What can we do to help them manage or get better?’”

Baby steps towards Embracing Precision Medicine in Paediatrics

The odds of diagnosing a rare genetic disease have increased over the years—thanks to next-generation sequencing technology. But more than half of patients with suspected rare genetic disease remain without a definite diagnosis^[2]. “Families of children with undiagnosed genetic diseases often go through a diagnostic odyssey which involves journeying through multiple doctors, multiple hospitals and multiple tests before they arrive at an answer. This is a long-drawn process that takes about 7.6 years on average, and at least two to three different diagnoses or misdiagnoses,” Dr. Jamuar says.

“Today, next-generation sequencing enables us to find answers to some of these genetic disorders. But as a scientific community, we are increasingly probing further to seek out other complementary technologies that can potentially help us diagnose and treat better with more targeted therapies.

“For instance, a patient with a rare disease called tuberous sclerosis may present with tumors in the brain and, in the past, the patient would have to go through multiple surgeries. Now, we can offer targeted therapy to shrink the tumour. Then there are cases where we can actually prescribe a gene therapy that can target the non-working gene and change its genetic configuration back to a normal copy. This is a new and exciting area—and we can be certain that the body of knowledge and application will expand in the next decade or so.”

The Future of Precision Medicine in Paediatrics and Medicine

Precision medicine, integrated into healthcare, has the potential to yield more precise diagnoses, predict disease risk before symptoms occur, and design customised treatment plans that maximise safety and efficacy. ^[3]

Dr. Jamuar says, “Our current clinical narrative goes like this—someone falls ill, sees the doctor, gets the diagnosis and receives medicine to manage the symptoms. It is reactive. In contrast, precision medicine is predictive and preventive. Instead of treating the illness when they manifest and health has already deteriorated to a certain extent, we pick up the disorders and institute treatment much earlier. In the process, we gain the opportunity to possibly change their health trajectory. “But that is not the only difference precision medicine offers. Besides the patient, it helps the family who share the same genetic composition to ascertain and understand their risks. For example, for a young couple planning to start a family, it helps them to know if their child has a 2%, 25%, or 50% risk of inheriting the disease.

“Foreseeably, precision medicine is what the future of medicine will look like,” injects Dr. Jamuar.

[1] Costain G, Cohn RD, Malkin D. Precision Child Health: an Emerging Paradigm for Paediatric Quality and Safety. Curr Treat Options Peds. 2020;6(4):317–24. doi: 10.1007/s40746-020-00207-2. Epub 2020 Aug 25. PMCID: PMC7445109.

[2] Vinkšel M, Writzl K, Maver A, Peterlin B. Improving diagnostics of rare genetic diseases with NGS approaches. J Community Genet. 2021 Apr;12(2):247-256. doi: 10.1007/s12687-020-00500-5. Epub 2021 Jan 15. PMID: 33452619; PMCID: PMC8141085.

[3] Johnson KB, Wei WQ, Weeraratne D, Frisse ME, Misulis K, Rhee K, Zhao J, Snowdon JL. Precision Medicine, AI, and the Future of Personalized Health Care. Clin Transl Sci. 2021 Jan;14(1):86-93. doi: 10.1111/cts.12884. Epub 2020 Oct 12. PMID: 32961010; PMCID: PMC7877825.