Strong Voices

Eight families have diagnoses for rare genetic disorders thanks to the latest work by a team of researchers at the University of Auckland.

The DNA of 25 people with undiagnosed intellectual disability from 19 families was studied using advanced genome sequencing and analytical methods. The project aimed to uncover the genetic causes of the neurodevelopmental conditions and improve the health of these individuals. The study was funded by the IHC Foundation.

Genome sequencing is a laboratory method of studying the genetic makeup of cells. The human genome contains a person’s complete set of genetic instructions.

As well as finding answers for eight families (12 individuals), the team believes it has broken new ground in a further four cases by identifying potentially novel genes or translocations involved in developmental delay. A translocation happens when a chromosome breaks, and the fragmented pieces reattach to different chromosomes.

No genetic diagnosis was found for seven of the 19 families, but analysis will continue in the hope of finding an answer for them.

The researchers from the University of Auckland’s School of Biological Sciences; Dr Jessie Jacobsen, Professor Russell Snell, Associate Professor Klaus Lehnert, Dr Whitney Whitford and PhD student Chris Samson, use whole genome sequencing to find a variety of genetic variations, including those that are complex – such as changes in the DNA that involve combinations of deletions, duplications or translocations of genetic material. The team worked with colleagues at Harvard Medical School and Massachusetts General Hospital in the United States to sequence and analyse the complex cases.

Whitney, who participated in the project on a post-doctoral fellowship funded by the IHC Foundation, developed a ‘bioinformatic pipeline’ (software to process the DNA sequences) to detect large deletions and duplications of DNA. She worked alongside Chris to validate and confirm the cases with deletions, duplications or translocations of genetic material.

Everyone inherits genetic variations that cause no difficulties. But when they do cause problems, the results can be devastating for the individuals and for the families affected.

Jessie is thrilled that the study has provided a potential answer for more than 50 percent of the families. “The research funded by the Foundation has been a huge success. Compared to much of the international literature, it’s a lovely statistic.”

Jessie says in two or three cases they discovered a new role being played by structural variants, where they don’t disrupt the gene itself but instead disrupt the non-coding regions nearby that interact with the key gene involved in the condition.

“Importantly, these results are contributing to the translation of this technology for routine use. Currently, we are applying to funding bodies to support the trial of this sequencing technology in the clinic, together with clinicians from Auckland District Health Board and Diagnostic Genetics at Auckland City Hospital.”

In 2015 the IHC Foundation funded the team’s pilot research project using genome sequencing to find the causes of rare, undiagnosed neurodevelopmental disorders. This early study found the genes and mutations responsible for rare conditions in 14 children. Following the success of the pilot, the Foundation funded the study in 2019 that has looked at even more complex variations.

New sequencing technology makes it possible to rapidly study large amounts of DNA at once. This has dramatically cut the cost of genetic detective work.

In 2001, it took years and cost $US95 million to sequence the whole human genome. Now it takes only days to sequence a person’s DNA and by 2021 the cost had been slashed to $US450, according to the US National Human Genome Research Institute.

“Now you can sequence the genome by chopping it up into small bits and sequencing them at the same time,” Jessie says. In New Zealand dollars the cost of sequencing the whole human genome is now around $1500 and the cheaper alternative of sequencing the human exome is $450. The exome is the protein-coding region that, while representing less than 2 percent of the genome, contains around 85 percent of known disease-related variants.

Jessie says cost-effective sequencing makes it possible to make the move from the research laboratories into clinics as part of normal diagnostic testing. She says finding genetic answers for families has been a real privilege and hopes this will tailor long-term management for those families involved.

Caption: Researchers from the University of Auckland’s School of Biological Sciences (from left) Dr Jessie Jacobsen, Dr Whitney Whitford, Associate Professor Klaus Lehnert and Professor Russell Snell.