Researchers Dr Jessie Jacobsen and Professor Russell Snell.

Families may be closer to discovering the genetic causes of intellectual disabilities affecting their children thanks to a University of Auckland research project being funded by the IHC Foundation.

A research team, led by Professor Russell Snell, Dr Jessie Jacobsen and Associate Professor Klaus Lehnert, of the School of Biological Sciences, is using the latest genome sequencing technology to look for a genetic diagnosis for children with undiagnosed, rare neurodevelopment disorders.

Twenty families from throughout New Zealand are participating in the two-year pilot study to discover the genes responsible for disorders that can’t be explained through standard tests. The IHC Foundation is meeting the $147,000 cost of collecting and reading the DNA.

“Sequencing is reading the DNA that is in all of our cells,” Russell says. “The great advantage of the new method is that you are reading all the pieces of DNA in one step. The magic is taking all of these small pieces and comparing them to a standard.”

A genome is the complete set of genetic instructions or genes contained in each cell. In humans, each genome contains all of the information needed to allow us to grow and develop.

“We get the DNA from either blood samples or saliva samples. We collect DNA from the parents, where available, along with the affected individuals,” he says.

The participants with intellectual disabilities are mainly children.

Only the individuals will have Whole Genome Screening, which looks at the complete set of DNA at a single time. “In the parents we sequence all the exome – the protein-coding regions. It’s approximately half the cost of sequencing the genome,” Russell says.

The exome in humans is about 1 percent of the total genome, but is thought to harbour about 85 percent of DNA variations that cause disease.

“The rationale behind that is that we expect to see variations in affected individuals. Some of the variations might be in the protein coding, but some of them might exist elsewhere.

“If we had more money we would sequence the whole genome in all individuals, but this group of cases will tell us how successful this more limited approach is,” he says. “For the current work the funding has come from the IHC Foundation, which is extremely generous. We are always looking for more funding as we have vastly more requests than we can support.”

The direct cost of sequencing is now as low as an overnight stay in hospital, but it’s not yet part of a routine approach to treatment. Russell says the aim is to build a case for making genome screening part of routine clinical practice for undiagnosed conditions and conditions likely to be inherited.

“Traditional gene-screening approaches, where you only select one gene at a time for analysis, are appropriate only for well-known conditions.

“The majority of conditions are rare and cannot be identified through this slow and expensive process. This leaves the patients and their families without a way to assess the risk of future pregnancies and can lead them on lengthy and costly diagnostic odysseys,”he says.

“Fundamentally, understanding the genetic basis of a condition is a very important first step towards the identification or development of a treatment.”

He says that a diagnosis can often help focus treatments.

Being able to put a name to a condition and to be able to describe causation can give families comfort and remove the worry that some environmental factor has caused a condition.

“Some families are interested in having more children, and finding a cause can mean they can make choices about having more children.

“We are working hand in hand with clinical geneticists across the country and we are building the evidence for the routine application of these technologies. Our hope is that as soon as a child presents with a developmental condition, the first port of call is that they will have their DNA sequenced if they choose.

“All the variations that we discover in our research lab are re-checked by the formal diagnostics laboratory and the results, if the patient or parents would like them back, are delivered through the formal genetics service,” Russell says.

The team believes that the new, cost-efficient genome-wide sequencing can dramatically increase the rate of genetic diagnoses in rare conditions.

In the course of this research project, the team is expecting to find the gene mutations responsible for neuro-developmental disorders in more than 10 of the 20 participating families. Russell says they can make that prediction based on past experience.

“There are some conditions where intervening early with a therapy can prevent longer-term damage.” Already the team has been able to identify two cases where early intervention has proved to be beneficial. “If the conditions were recognised from birth, the benefit of treatment could have been even greater,” he says.

“As a group we are quite good at identifying causal DNA variants now, and at least as efficient as the best groups in the world. This is because we are a research group. We spend more time on each case than a diagnostic laboratory can currently. However, with the experience being gained through our work and internationally, the process is becoming increasingly efficient.”