DNA detectives: the Otago scientists decoding ultra-rare genetic disorders

A global revolution in genetic sequencing is helping University of Otago scientists solve the mysteries of ultra-rare disorders, for one family at a time.

It’s called the diagnostic odyssey: an exhausting, seemingly endless journey from one specialist to another, in search of an explanation for a child’s debilitating and confounding symptoms.

Those might range from developmental delays to seizures or vision loss, and the struggle for a diagnosis might last years or even decades – if it ends at all.

For families impacted by rare disorders, of which there are an estimated 7,000 to 10,000 different types, it’s an unfortunate and all-too-common reality.

Collectively, these touch the lives of several hundred million people, yet the vast majority lack an approved drug treatment. Around three-quarters are genetic, meaning they can be present from birth even if symptoms don’t appear until later in life.

Now, a revolution in genetic sequencing technology is increasingly helping families find the answers they desperately seek – and University of Otago researchers are working at its forefront.

In the early 2000s, sequencing the first human genome – or decoding our entire genetic make-up – was an international effort that cost billions of dollars and took years to complete.

Two decades on, scientists can sequence an individual genome for just NZ$850, opening up a new world of possibilities in pin-pointing the precise genetic causes of rare disorders.

As Associate Professor Louise Bicknell explains, these typically come down to small alterations, or ‘typos’, hidden among a person’s DNA.

Her lab in Otago’s Faculty of Biomedical Sciences uses DNA from families who have gone through the clinical system without a diagnosis. Once they find an alteration in the DNA, they start looking for others with the same change.

Due to the sheer rarity of these disorders – Meier-Gorlin syndrome, of which Louise’s team has identified most of the genes involved, is known in only 80 patients worldwide – this search often stretches far beyond our shores.

“You can’t just rely on finding another New Zealand family,” Louise says.

“There might be only 10 cases in the entire world.”

To find these other cases, Louise uses a global research platform she jokingly calls a “dating site for geneticists”.

Here, scientists input a gene and are matched with others who have also found alterations in the same gene.

“Even on a Friday afternoon, I put in a gene name and get possible matches. I can email back and forth with colleagues, and think, ‘there could be five patients that might match ours’,” she says.

“That’s really exciting. It’s a real adrenaline rush.”

It’s a system that has led to some significant breakthroughs.

Most recently, Louise’s team discovered a variation in a gene called CRNKL1, which causes a rare and severe neurological disorder that profoundly impacts brain growth and function in children.

Beginning with a young New Zealand girl, the researchers eventually identified 10 families worldwide, nearly all of whom carried the exact same change.

Not only did the discovery offer further clues into the complex ways our genes guide brain development – it provided the families with a sense of community, and invaluable insights about the likely prognosis.

“It gives them hope. By building up a bigger number of patients, you can build up information about the condition, which is so important for the families,” Louise says.

“Things like, ‘Yes, they'll grow to be an adult,’ or, ‘No, their condition won’t improve, but nor will it get any worse’.”

Decoding Batten disease

While Louise’s work is like a global hunt, Professor Stephanie Hughes has spent much of her career focused on a single group of diseases: Batten disease.

Like many rare disorders, Batten disease can take years to diagnose, as its early symptoms, ranging from blindness to seizures, are often mistaken for other conditions.

“It's a nightmare not to know,” Stephanie says, explaining that even when a diagnosis is finally made, many clinicians have no expertise in the disorder, leaving families to rely on overseas support groups or “Dr Google”.

While gene therapies have been developed for some forms of Batten disease, including a clinical trial which was initiated in her lab. However, Stephanie and her international colleagues still don’t know what the genes themselves do.

“We’ve got a few treatments now, but scientists are now moving back to the lab to try and understand the disease and gene functions in a lot more detail.”

This has revealed surprising insights about the disease, such as the fact it affects the gut and not just the brain.

“The gut has more neurons in it than the brain does, so it’s not surprising that if you've got a neuronal disorder, you’d also have a gut disturbance.”

For Stephanie, the research is intensely personal.

For more than 20 years, she has kept in close contact with New Zealand families she worked with – a bond that’s common in the rare disease research community.

The Otago team’s work also highlights a major advantage of being based in a small nation –greater collaboration between researchers across disciplines.

This cross-pollination of expertise led to the creation of RARITY, a University of Otago initiative aimed at bridging the gap between rare disease discoveries and real-world clinical treatments.

Louise also recently led the charge to make the university a member of the Horizon Europe funded consortium ERDERA – the largest rare diseases research programme in the world.

It’s an “amazing” opportunity for local researchers to learn from their international counterparts, she says – but it’s also highlighted New Zealand’s comparatively little science funding and resourcing in the area.

“When you see that lot of countries are investing in this space, there is a risk of New Zealand being left behind,” Louise says, adding that research here is nonetheless globally recognised.

She also points out the Eurocentric bias in global research databases, which makes New Zealand's unique genetics and approaches a valued contribution.

Both researchers say another major obstacle is the under-resourced clinical diagnostic system, which often forces families to wait for years, or seek answers in the research environment.

“We work with a lot of families for whom we can find answers quite quickly: that’s fantastic and it’s what we love,” Louise says.

“Ideally, these should be getting picked up clinically – but there just hasn’t been the investment to support adequate clinical diagnostics here.”

For this reason and many others, Louise and Stephanie say their labs’ mission is far from over.

“There are always more patients, and more families, to help.”