Approximately 80 per cent of rare diseases are estimated to have a genetic origin. PHOTO: ST FILE
SINGAPORE – The girl was 10 years old before she was finally able to say "papa" and "mama", and feed herself using a spoon.
She was also smaller in stature compared with her peers, standing at 1.16m and weighing under 16kg.
For years, she was a medical mystery: Doctors could not explain what led to the significant delay in her developmental milestones.
The teenager, who has been seen by doctors from the KK Women's and Children's Hospital (KKH) since infancy, underwent the usual clinical investigations like blood tests and brain MRIs – all yielded no clear diagnosis.
But her symptoms gave them a clue as to where to look – in her genes, for a possible underlying rare genetic disorder.
Explaining why a delay in developmental milestones is often linked with genetic disorders, Associate Professor Tan Ee Shien, head and senior consultant at KKH's genetics service, said: "When and how a child learns to walk, talk and develop social skills – these are all very much determined by the maturation of the brain.
"The development of the brain and all its neural connections is a complex process that involves many different genes and biological pathways. Therefore, when there is a genetic mutation, the brain is one key system that is affected."
The girl was enrolled in a KKH programme called Bridges, or Bringing Research Innovations for the Diagnosis of Genetic Diseases.
The initiative was set up in 2014 to help children with suspected rare genetic disorders find a diagnosis.
Its work is done in collaboration with genomic research institutes such as the Agency for Science, Technology and Research.
Approximately 80 per cent of rare diseases are estimated to have a genetic origin.
In Singapore, a rare disease is defined as a condition that affects fewer than one in 2,000 individuals. Around 2,500 people here are estimated to have a rare disease.
The teenage girl turned out to be among them. Using a technique called whole exome sequencing, which allows for the identification of genetic variants across many genes in a single test, Bridges’ researchers saw mutations in the DRG1 gene.
Working with international researchers, Prof Tan was able to prove the effect of the disrupted DRG1 in patients.
An article on the newly discovered disease, named Tan-Almurshedi syndrome after Prof Tan and another researcher, was published in the Genetics In Medicine journal in 2023. Including the Singaporean patient, there are only four known cases in the world.
Tan-Almurshedi syndrome is one of five previously unknown genetic diseases discovered through the Bridges programme. The others were found between 2016 and 2020.
Principal genetic counsellor Lim Jiin Ying (left) and senior consultant for paediatric genetics Dr Saumya Jamuar at KK Women's and Children's Hospital on Sept 9. ST PHOTO: KEVIN LIM
Since Bridges' inception in 2014, more than 700 families have been screened, and as at 2024, 49 per cent of them have received a diagnosis.
This is higher than the 39 per cent diagnostic rate in 2020 – an improvement Associate Professor Saumya Jamuar, a senior consultant at KKH's genetics service, attributed to leaps in technology.
Emphasising the importance of getting a diagnosis for patients, Prof Tan said: "This helps the doctors to better plan their management of the patient with more focus. This sometimes also allows for patients to avoid unnecessary tests.
"For example, in the case of patients with Tan-Almurshedi syndrome where poor growth is common, we will not need to conduct multiple blood tests to look for the reason behind it."
She added: "Also, knowing the gene responsible, we are then able to identify the biological processes it affects and, hence, take that first step to look for potential therapeutics."
Knowing the underlying genetic basis of a disease also helps healthcare workers to provide genetic counselling to affected families, Prof Tan said. This will enable families to understand the risk of having another child with the same disease.
Depending on the condition, there is a 2 per cent to 50 per cent chance of parents passing on a genetic disease to their children.
"Whenever parents have the diagnosis of a rare disease in their first child, they want to know whether the condition will impact the second child. They want to know the child's medical needs, the implications on their learning and development, and family planning options available to them," said Ms Lim Jiin Ying, principal genetics counsellor at KKH's genetics service.
Options for these parents who want children range from adoption, to using a sperm or egg donor, to doing invasive tests during a pregnancy to detect conditions.
If couples choose conception via in-vitro fertilisation, they can screen their embryos for specific genetic changes before implantation in a process called pre-implantation genetic testing.
"There are always ethical considerations when we are talking about family planning. If they are pregnant, we don't direct them to continue or terminate the pregnancy. But giving them information is key, and we will discuss issues like resources available for psychosocial and financial support," said Ms Lim.
But while Bridges helps families whose children are afflicted with rare disorders to find answers, the genetic tests are currently offered only after a child in the family is born with a severe disorder.
Prof Jamuar hopes that genetic testing technology can be better leveraged to inform more couples and families of their risk of having a child with a severe genetic condition, so that they can be better prepared to handle the risk.
One area that could be possibly looked into is screening for recessive genetic disorders, he said.
In recessive genetic disorders, a child would have inherited two copies of an abnormal recessive gene – one from each parent. Very often, parents with an abnormal recessive gene, who are also known as carriers, may not know that they have such a genetic trait.
"Because both parents are healthy, nobody knows that they are carriers," said Prof Jamuar.
A couple who are both carriers have a 25 per cent chance of having a child with that genetic disorder.
"In carrier screening, the idea is that we can identify these couples before they have the child, so they're informed and can make better decisions about their pregnancy, knowing what their risk is," said Prof Jamuar.
He added: "If they decide not to do anything, that's perfectly fine, but at least they know about it."
He cited thalassaemia screening as an example of pre-emptive action – subsidised tests have been offered to couples planning to start a family with the setting up of the National Thalassaemia Registry in 1992.
Those with the condition are not able to produce normal haemoglobin, and need a blood transfusion every month. About 3 per cent of Singapore's population are carriers of the thalassaemia gene.
With screening, the incidence of babies born with thalassaemia has fallen over the years.
"We are not trying to make sure that no babies with thalassaemia are born. But what we're doing is informing couples and giving them the risk assessment, so they can make their own choice," said Prof Jamuar.
Source: The Straits Times © SPH Media Limited. Reproduced with permission.
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THE STRAITS TIMES © SPH Media Limited. Permission required for reproduction
