New approaches to gene hunting turn up answers in rare diseases

20 Dec 2013

Dr Jillian Casey, associated researcher with the UCD Academic Centre on Rare Diseases. Photo by Peter Casey

Dr Jillian Casey is using new techniques to analyse genes involved in rare diseases. She spoke to Claire O’Connell about her work as a gene hunter.

It’s the genetic version of finding a needle in a haystack: pinpointing the subtle but all-important change in DNA ‘letters’ that mean a person has an inherited genetic disease. But Dr Jillian Casey has technology on her side to find those tiny variations. In recent years, she has helped to find the genetic mutations involved in several inherited rare diseases in families in Ireland, and she is keen for students of genetics to get to grips with the new tools of the trade.

An eye to new technology

Casey herself hit the ground running in 2008 when she started her PhD with Dr Sean Ennis in University College Dublin (UCD). Ennis and his group had long been working with families to find the genetic causes of inherited rare diseases, but in some cases the answers were waiting for the technology to catch up with them.

“In one family, several children had been born without eyes, and the family had been waiting for nine years to find out what genetic variant was at the root of it,” recalls Casey. “The traditional approaches to genetic analysis had ruled out the ‘known’ disease genes for this eye disorder, so we knew it was a new gene in this family but we didn’t know where it was.”

Casey used a newer technique – SNP genotyping – on DNA samples from the family to look for regions of DNA that were shared by the affected individuals but not the healthy relatives. That approach quickly narrowed the search down to one region of DNA containing about 15 genes.

“After nine years of looking for this genetic variant in this family, the new technology suddenly allowed us to make this breakthrough within a week,” she says. “And two months later, using next-generation sequencing technology, we had found the actual mutation, which was in STRA6, a gene involved in vitamin A uptake and eye development. Once we had the right technology, it jumped out pretty much immediately.”

During her PhD at UCD and post-doctoral research studies at the National Children’s Research Centre at Our Lady’s Children’s Hospital in Crumlin, Dublin, Casey helped to hunt down genes in other rare inherited diseases, too, including a liver disorder and a glucocorticoid deficiency that can affect growth. She has just started work as a research associate at Temple Street Children’s University Hospital, where she will continue to look for the genes responsible for rare disorders affecting children.

Boosting bioinformatics

One of the big challenges is to analyse the mountains of genetic data that even a tiny sample of DNA can generate. Since Casey studied genetics as an undergraduate in University College Cork the landscape has changed and she has to keep up to date not only with the ‘wet lab’ skills but also the bioinformatics involved in analysing the results. “Bioinformatics is a very important aspect of what we do,” she says. “A lot of people are terrified of bioinformatics, but it has a huge value for the study of genetics and I’d recommend to any student with an interest in genetics to take modules in bioinformatics.”

Casey has recently been working to boost student education in the area at UCD, where she is an associated researcher with the UCD Academic Centre on Rare Diseases (ACoRD). She is developing lectures and computer practicals on next-generation technologies and the associated bioinformatics tools. “I’m excited about it – I think the students will enjoy the challenge of working with mocked up data and trying to sort through variants to find the one disease mutation,” she says. “It will be a brain sharpener and a more enjoyable method of learning and applying bioinformatics tools.”

The right diagnosis

Casey doesn’t meet the people whose DNA she analyses, but she works closely with Genetic Consultant Dr Sally Ann Lynch at the National Centre for Medical Genetics, who liaises with the families and is involved in clinical interpretation of the data.

And it is of utmost importance to make sure the genetic diagnosis is correct, says Casey. “You have to remember there is a patient behind this and if you are wrong then there are the consequences for the patient,” she says. “No diagnosis is better than a wrong diagnosis.”

Even if there is currently no cure, getting the genetic diagnosis can offer a sense of closure for the families, she notes, and in some cases knowing the genetic basis can help to identify more options for managing the condition. Plus, knowing the genetics can make diagnostic testing easier.

“A simple blood test could offer a less invasive route for family members to find out whether they carry the disease-causing genetic variant,” she adds. “And more generally, knowing these genetic details could be important information for potential future therapies, too, should they become available.”

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Dr Claire O’Connell is a scientist-turned-writer with a PhD in cell biology and a master’s in science communication