A geneticist at Our Lady's Hospital for Sick Children has discovered the gene responsible for a disorder that causes a birth defect, writes Dick Ahlstrom
Clinical physicians have an important part to play in medical research, as they see the results of disease. They can spot possible connections between patients' symptoms that aren't seen by laboratory-based researchers.
A recent example of this resulted in the discovery of the genetic mutation that causes a birth defect of the hand. Dr William Reardon, consultant clinical geneticist at Our Lady's Hospital for Sick Children, in Crumlin, led the research.
"I had some idea about what gene it might be," says Dr Reardon, who takes a special interest in hearing problems and saw many children with congenital birth defects while working at Great Ormond Street Hospital for Children, in London. "I am a geneticist, so I see children with syndromes."
He conducted the research with colleagues at the University of Göttingen and at the Institute of Child Health in London, which has close links with Great Ormond Street.
"The Children's Medical & Research Foundation of Our Lady's Hospital for Sick Children in Crumlin supported the work," he adds.
The disorder in question is Okihiro syndrome, named after the Japanese doctor who first described it. Children with Okihiro syndrome are commonly deaf and have malformed hands, along with problems relating to eye movement that gives them a squint.
How common the syndrome is here is difficult to pin down, Reardon says, because it is often diagnosed as something else. About one in 1,000 children here is born deaf and, of these, almost half have a syndrome of deafness.
Okihiro syndrome is one of these syndromes of deafness in childhood, but children with it also have the other features of squint and arm or hand abnormalities.
Reardon's experience with young patients, first in London and then in Crumlin, helped him draw conclusions about the gene responsible for the syndrome. Okihiro syndrome is quite difficult to diagnose, because symptoms vary and overlap with other disorders.
The way to tackle this problem was to think in terms of disease families and gene families connected to them, he says.
Earlier work had identified a variety of malformations linked to a gene known as Sall1, he explains. "I could think of several mutations that are related to Sall1. Our hypothesis all along was a Sall gene was the cause of Okihiro syndrome."
The research team pursued this single theory rather than trying to prove what genes were not responsible, thus narrowing the search. "We searched DNA databases provided by the National Institutes of Health, the University of Washington and others. All of these databases would have been established under the Human Genome Project."
Three Sall genes had been discovered and the team looked for others that bore the hallmarks of the gene type. "It has a certain motif, like a PIN number that allows it to be classified as a Sall gene," says Reardon. All in the gene family share "essential core elements" and they scoured the databases looking for genes with a similar motif.
They found what they were looking for on chromosome 20, then set up a series of experiments using Okihiro syndrome patient samples to confirm the new Sall4 as the cause. They quickly discovered that Sall4 was indeed responsible for Okihiro syndrome.
"One of the most difficult things in genetics is proving cause and effect," he says. "For the first time ever we have established cause and effect" for the syndrome.
The team, which published their findings in Human Molecular Genetics, also cloned Sall4. This gives clinicians and researchers a powerful new tool.
"It gives us a diagnostic test we can apply in the laboratory," he says. Samples of the gene from a patient with suspected Okihiro syndrome can be compared to the cloned gene to confirm a diagnosis.
It can also help sort out the root cause of children presenting with a squint, so more serious genetic disorders can be ruled out.
And it gives researchers important new insights into the highly complex process that produces limbs in the growing foetus. "It allows us to add in one further piece of the jigsaw on the development of limbs."