Hunt for facial deformity gene ends after 20-year search

A new disease gene discovery began with a Perth PhD student and the world’s largest known family with the disease. Twenty years later Yale University U.S.A. re-found that research, compared it to affected American families, asked the Perth team to re-look at the original DNA and found a match.

Hunting for disease genes is like putting together an international jigsaw puzzle. The DNA of families across the globe often contributes to the necessary process of cross-referencing discoveries of tiny segments of genetic code to see if they match.

One of the world’s best, Professor Nigel Laing AO at Perth’s Harry Perkins Institute of Medical Research says it’s a Eureka moment whenever a discovery is made.

“In that moment you know you are looking at something no-one else has ever seen, the precise genetic mutation causing a disease that’s affecting families around the world and when you make that discovery you know those families will finally get the answer that they have longed for,” he said.

Families with hemifacial microsomia, a condition where one side of the face is underdeveloped and does not grow normally, have just joined that rarefied group.

Their disease gene has been found.

For the first time families affected by the condition will be able to find out if they are passing it on to the next generation.

Hemifacial microsomia is the second most common facial congenital disability after cleft palate. It affects one in every 3,500 to 4,000 births.

In a very small number of cases, hemifacial microsomia is inherited in an autosomal dominant pattern, which means one copy of an altered gene in each cell is sufficient to cause the disorder. For an adult with the affected gene, each of their children has a 50 percent chance of inheriting the condition.

The disease develops in utero and babies born with facial deformities can need breathing support or a tracheostomy soon after birth if the jaw is severely affected. The condition does not improve with growth, in fact deformities can get worse.

Children with hemifacial microsomia have an increased risk of hearing loss, speech impairment, and feeding problems and, unsurprisingly, can experience psycho-social challenges in childhood.

The hunt begins

Twenty years ago, a hunt for the disease gene began in Perth, Western Australia.

PhD student, now Dr David Chandler, started working with the biggest known family with the condition.

Nine members of the same family were affected. They had been seen by Genetic Services WA, the Department of Health’s clinical genetics service, which works with families to diagnose their condition if possible and provide genetic counselling if wanted.

David Chandler commenced the arduous process of analysing the family’s DNA for clues about what might be causing this genetic disease to see if a diagnosis could be made.

His PhD was supported by a UWA PhD Scholarship and by the National Health and Medical Research Council (NHMRC) Project Grant associated with the NHMRC Fellowship that Professor Laing held at the time.

Internationally renowned geneticist Professor Nigel Laing AO, Head of the Genetic Disease Group at the Harry Perkins Institute of Medical Research, jointly supervised the PhD.

At the time the technology available, limited the search.

“We could narrow down the hunt from three billion base pairs of DNA to 14 million.”

Professor Nigel Laing AO

“We were looking for DNA markers shared by everyone who had the disease and David Chandler found that on a region on a particular chromosome, but without the genetic sequencing technology available today, it wasn’t possible to refine the search further.”

“We also needed to cross reference our findings with other families with the condition. We knew of research in Germany but it looked like that family’s condition was on a different chromosome,” he said.

Despite not being able to take the research further the proposed chromosome region of the gene was published in 2001.

Two decades later

Dr David Chandler was awarded his PhD and now works at the Australian Genome Research Facility at Royal Perth Hospital.

Professor Laing is Head of the Preventive Genetics Group at the Harry Perkins Institute of Medical Research where his lab has been involved in the discovery of more than 30 disease genes including one that bears his name, Laing distal myopathy, a condition that causes progressive muscle weakness from childhood.

Professor Laing’s team variously receives support from the NHMRC through Fellowship, Project and Ideas Grants and the Medical Research Future Fund.

In recent years the team has also been generously supported by The Fred Liuzzi Foundation in Melbourne, The Zac Pearson Legacy in Perth and the family of the late Dr Patricia Kailis AM, OBE, FTSE who conducted world leading genetic research before the mapping of the human genome had occurred. Dr Kailis recorded the world’s first decrease in the incidence of an inherited disease as a result of genetic counselling.

Her family has established the Patricia Kailis Fellowship in her honour to provide funding for mid-career researchers focused on unlocking the secrets and providing treatments for rare genetic diseases.

The link with America

Last year the senior authors on the West Australian 2001 paper were contacted by Professor Andrew Timberlake at Yale University in the U.S.A.

His laboratory had been analysing the genetic code of six other families with hemifacial microsomia, mostly from the USA.

“He said he had identified a possible gene for hemifacial microsomia in the region on the chromosome that matched the region identified 20 years before in our research,” said Professor Laing.

“Professor Timberlake found variants which knocked out the function of a particular gene affecting the growth patterning that influences facial development.

“He’d scoured the published literature and found our 20-year-old research and contacted us.

The Yale University group were very keen to know whether the Perth family’s DNA had been kept and could be again accessed. They were still believed to be the largest affected family in the world.

The answer was yes.

“We still had DNA of members of the Perth family and Genetic Services WA recontacted the family and updated the family tree which now had 12 affected family members.

“Collaborating with Diagnostic Genomics in Pathwest we discovered that the Perth family also had the function of the gene knocked out.

“Finally, we could say that the gene causing hemifacial microsomia had been found.”

Professor Laing

Dr Chandler was delighted that his research as a young student had resulted in an international discovery.

“It is incredibly exciting to have a genetic search that commenced such a long time ago resolved for families around the world,” Dr Chandler said.

Professor Laing said the discovery gives couples with a history of the disease in their family reproductive choices.

The 2021 research has been published in Nature Communications

Professor Nigel Laing and Dr David Chandler discuss finding the hemifacial microsomia gene

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