Tracking mutated genes that wreak havoc

When Mrs Evelyn Lim's four-month-old son Jason (not their real names) had a lung infection, his constant crying was not the worst of her nightmares.

Doctors found something more shocking - that Jason, who was born smaller than other babies, had an extremely low platelet count.

While a normal person's platelet count is 150,000 per microlitre of blood or more, Jason's was only slightly more than 75,000. And still it went into a downward spiral.

Since platelets are essential for blood to clot, Jason, barely a few months into life, was in critical danger with the slightest fall or knock.

"His blood cell levels were very low and there was a high risk of severe bleeding and serious infection. We were really concerned," said Dr Rajat Bhattacharyya of KK Women's and Children's Hospital (KKH), where he was treated.

The toddler's condition was so dire, he needed weekly blood transfusions at the hospital.

Not only did the $2,000 weekly bills take a toll on family finances, Mrs Lim's social life also took a hit.

"It was always home, then KKH, seldom anywhere else," she said. "I did not dare to take him out, especially to crowded places."

Five months of extensive testing shed no light on why he was ill.

That was when Dr Saumya Jamuar of KKH recommended a special genetic test called exome sequencing, with help from scientists at the Agency for Science, Technology and Research (A*Star).

This test helps scientists "read" part of the human genome, which contains the most critical parts (the exome) that determine how we look, how our bodies function and in some cases, our physical abnormalities. With this, scientists isolate which single gene mutation could have caused the disorder.

The tie-up was one which the hospital and A*Star had embarked on for children suffering from rare and baffling diseases.

It turned out to be a good call. After analysing Jason and his parents' genetic samples, and talking through his case with his doctors, the team - within a month - was able to find the mutated gene that was wreaking havoc.

It gave the family an answer to Jason's problems. And more importantly, it confirmed that a stem cell transplant, which he eventually had, would cure him of his life-threatening blood problems.

"It was such a relief to find an answer," Mrs Lim said. Jason will still have learning problems as he grows up. "But at least the life-threatening part of his condition was removed."

The exome sequencing project has brought hope to parents like Mrs Lim, whose children suffer from illnesses their doctors might not have encountered. Only about 50 people worldwide suffer Hoyeraal-Hreidarsson's syndrome, a condition similar to Jason's.

"Some illnesses are ultra-rare. We might have read of cases in textbooks and journals, but when faced with the real thing, it is hard to determine," said Dr Angeline Lai, who heads KKH's genetic service.

Once a child is thought to have a genetic disease, KKH doctors will put him through the first line of tests, especially if more common ones like Down syndrome and thalassemia, a blood disorder, are suspected. About 5 to 10 per cent of cases will be diagnosed here. If nothing comes up, patients are put through a second set of tests.

In the second round, about 15 to 20 per cent of patients would be diagnosed. There may not be a treatment but doctors can keep managing the symptoms. With A Star's exome sequencing test, parents may have an additional 30 per cent chance of finding an answer. "When your child is in a life-threatening situation, every chance counts," said Mrs Lim.

A*Star has sequenced samples from 159 families at KKH since 2013 and found the gene mutation in about one in three cases. The test is also available through the National University Hospital, where about 35 cases have been sequenced, said Dr Bruno Reversade, senior principal investigator at the Institute of Medical Biology (IMB).

When the genetic analysis sheds light on a problem, it helps immensely, said Associate Professor Roger Foo, group leader at the Genome Institute of Singapore. "Often it takes away distress, a dark cloud is lifted," said Prof Foo, whose institute is partnering the IMB on the project.

A*Star and the hospitals' (KKH and NUH) life-saving partnership started with Dr Reversade's quest to understand rare diseases as a means to a better understanding of common ones (see other story).

For the Genetic Orphan Diseases Adopted: Fostering Innovation Therapy project that he leads, he was awarded a large grant, which has funded the cost of genomic sequencing. The test, which costs $1,500 to $2,500 per person, is free for the families.

In the process of genomic sequencing, scientists decode only 2 to 3 per cent of the human genome. This small fraction is known as the exome, which harbours most of the important regions where some rare disorders can be detected.

In exome sequencing, blood samples are typically taken from the parents and child. The DNA is extracted, sequenced and analysed for the individual's genetic make-up. Then comes the part where scientists work together with doctors to play "medical detective" and investigate if a genetic mutation spotted may be the cause of the problem.

Yet, the diagnosis rate is still just 30 per cent, as modern medicine does not have all the answers to all rare diseases, especially those involving multiple gene mutations, said Dr Reversade.

Genetic mutations may also occur in parts outside the exome, and that requires whole genome sequencing - reading a person's full "code book" - to detect.

"It's much more expensive and there is a lot of data to manage, but we are already working towards it." A child's symptoms such as cleft or facial deformities may also look like the result of a rare genetic disease, but could be due to other causes like trauma during foetal development.

Even if a diagnosis can be arrived at, it does not mean a cure is available. But by comparing the genes of parents and child, scientists and doctors are able to tell if the genetic mutation would likely recur in future offspring. "It helps the couple plan or even decide if they want future pregnancies," Dr Lai said.

In some cases, the results may give surgeons more confidence to go ahead with major operations, reassured that abnormalities would not recur post-surgery.

One case stands out for the team. It involved a girl just over a month old, who landed in hospital week after week for infections of all sorts, from the lungs to the liver to the lymph nodes. One infection was so severe that she required extensive surgery to remove some skin on her buttocks, said Dr Saumya.

A team of 10 doctors could not figure out what was going on. "But the prognosis was bad and she needed urgent help," Dr Reversade said. Knowing that a life was on the line, some of his team members came back on a weekend just to analyse the results of the genetic test.

In a week, scientists and doctors found the mutated gene, which was associated with the patient's sweat glands and immune system. They were able to recommend a stem cell transplant which, like for Jason, saved the girl's life.

"It's rare that science translates and saves a person's life so quickly," said Dr Reversade. In contrast, it might take a decade to develop a successful drug for illnesses. "This is one of the exceptions, but it is a dream for doctors and researchers. We really live and thrive on it."

cheongkash@gmail.com

This article was first published on September 18, 2015.
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