Image: Liver Biopsy from UCD Study. Bubbles indicate fat globules (abnormal) 

Dr. Sally-Ann Lynch, Consultant Geneticist at Our Lady’s Children’s Hospital Crumlin and a member of the UCD research group, said the findings will have a positive impact for a small but vulnerable group of children.

 “This disorder, known as infantile hepatopathy affects approximately 1 in 2,500 live births and can be life-threatening. Children who present with symptoms of this disorder are usually very sick, and the use of biopsies is a painful, stressful and sometimes risky procedure. This new test is a non-invasive diagnostic tool, and an excellent example of research translating directly to a clinical setting,” said Dr. Lynch.

Using a combination of genetic analysis techniques, the research team identified a mutation in the LARS gene - an enzyme involved in generating essential cell proteins - that causes rare infantile liver disease.

“To develop better therapeutic treatments we first need to understand the disease mechanism. The symptoms of this infantile liver disorder include anaemia, developmental delay and seizures. When we see multi-system symptoms of this nature, it suggests a dysfunction in the mitochondrion, the so-called ‘power house’ of the cell. Our research rules that out, and identifies instead a mutation in the protein-making LARS gene as the primary cause. That knowledge will inform the future development of how we treat patients,” said Dr. Casey.

These ancient protein-making molecules have been implicated in a number of human disorders including neurological diseases, muscle disorders and cancers. This is the first time that one of these molecules has been associated with a liver disease. 

Reference

Our researchers have had a key role discovering a gene variant that makes people with cystic fibrosis (CF) five times more likely to develop liver cirrhosis and other liver complications than patients who carry the normal version of the gene.

'We are really excited about this breakthrough,' says Dr Marion Rowland, Principal Irish researcher on the study. 'About five per cent of CF patients develop liver disease that is so severe it requires a liver transplant. This discovery could lead to earlier detection and diagnosis of cystic fibrosis liver disease which would result better treatment options for the patients affected by the disease,' she explains.

Cystic fibrosis is the most common fatal genetic illness among young Irish people. It affects 1100 people, but it is still a rare disease. Patients with the illness have defects in a particular gene called CFTR. This defect cause the lungs, intestines and pancreas to become clogged with mucus, resulting in breathing problems and other difficulties.

'Without the Health Research Board funding targeting rare diseases we would not have been in a position to contribute in such a significant way to this international study,' says Dr Rowland. 'While the HRB provide funding for research conducted primarily in Ireland, it recognises that those investigating rare disorders, may need to participate in projects that are led predominantly and perhaps even fully outside of Ireland.'

'By teaming up with other organisations in Canada and North America, we were able to compile the largest ever number of samples from CF patients with liver disease in order to test our theory that genes other than CFTR affect the development of liver disease in CF patients,' she explains.

The study was initially conducted among 124 CF patients with severe liver disease and 843 CF patients without liver disease. The team then examined the  variants among five genes that are thought to be associated with liver disease. They discovered that more CF patients with liver disease had a gene variant called Zallele, than those CF patients who did not, indicating that this gene has a role to play in the development of liver disease. In order to confirm the results they repeated the same test with a different group of 136 CF patients with liver disease and 1088 patients who did not. Their finding was the same, verifying their original findings.

'Further research will be required before we can definitively identify those who are at risk,' says Prof Billy Bourke (UCD School of Medicine and Our Lady's Hospital for Sick Children, Crumlin). 'But this is a really important discovery which provides clear direction for where we need to focus our next research effort. Ultimately we want to provide early diagnosis and save lives'.

'Without participation of patients and their consultants, Dr Charlie Gallagher in St Vincents, Hospital and Dr Gerary Canny in OLHSC, this work would not have happened,' says Dr Rowland.

This study was funded in part by the Health Research Board in conjunction with the Children's Medical and Research Foundation under the umbrella of Irish Charities Group for Research in Rare Diseases. International funding to support the research also came from the International Institutes of Health in America and Genome Canada.

The international study is published in the Journal of the American Medical Association (JAMA).

Source : www.hrb.ie

Our researchers have for the first time identified a series of rare genetic events that may contribute to the development of Autism Spectrum Disorder (ASD). Dr. Jillian Casey from UCD, lead author of the study within the international autism consortium, made the discovery after developing a new method to analyse complex genetic disorders. 

As reported in Human Genetics (April 2012), 310 genes were identified that may contain rare variations contributing to ASD. Ten of these genes had previously been implicated in ASD and 300 represent new candidate genes for the complex disorder.

Autism spectrum disorder is notoriously difficult to categorise. Factors contributing to ASD are highly variable and complex, and the symptoms of the disorder vary hugely from person to person. International efforts to identify a common genetic cause for ASD have been largely inconclusive. This new discovery represents a significant step towards understanding the complex set of genetic factors responsible for ASD.

Most international genetic research on autism spectrum disorder has concentrated on identifying and attempting to map common gene variants. This approach has worked well in identifying genetic factors related to diseases like Alzheimer’s, macular degeneration, type 2 diabetes and Crohn’s disease. However, in the case of ASD no conclusive common genetic cause has been found among people who experience the disorder.

Image: Dr. Sean Ennis

“We might typically look for a stand out gene or a combination of genes that are altered in people with a particular disorder. We know from previous studies that this is not possible with ASD, you could look at 100 different people with ASD and there might be no significant genetic commonality,” said Dr. Sean Ennis, from the UCD School of Medicine and Medical Science, and co-author of the research.

Instead of trying to identify genes that are common in people with ASD, Dr Ennis and his team developed a complex genetic analysis – known as homozygous haplotype mapping - to identify rare genetic events that were shared within very small sub-sets of the main sample group. This method searches for rare recessive disease genes, whereby the affected child has inherited two defective copies of a gene.

“We know that no one gene alone contributes to autism spectrum disorder so this method allows us to drill down into the genetic data and start to identify very tiny sets of shared genetic characteristics amongst people with ASD. Each of these tiny sets – they might involve just 2 or 3 per cent of the sample ASD group – is then compared to a non-ASD control group to see if the genetic variation can be considered usual, or if it might be seen to appear at a higher than usual rate in people with ASD,” said Dr. Casey.

Dr. Casey described the discovery as “a small but significant step in the right direction” towards understanding the genetic cause of autism. 

“If we can use this method to identify rare candidate genes associated with ASD, then we may at some point be able to link specific genes to particular aspects of autism,” said Dr. Casey.

Dr. Ennis and his research team are now using the method they developed to study other complex disorders including Alzheimer’s disease and bipolar disorder.

Scientific Journal Article:

A novel approach of homozygous haplotype sharing identifies candidate genes in autism spectrum disorder Published in Human Genetics, April 2012.

Research Team

The research team also included Professor Andrew Green, Consultant in Medical Genetics at Our Lady’s Children’s Hospital, Dublin, Ireland, Professor Louise Gallagher from Trinity College Dublin and Professor Michael Gill, Institute of Molecular Medicine, Trinity College Dublin. 

More information on Autism Spectrum Disorder

Autism is a condition which is characterised by severe problems in communication and behaviour and an inability to relate to people in a normal manner. Autism apparently occurs more frequently in males. Surveys reveal a general incidence of about fifteen in every 10,000 children. It can be suspected as early as a few weeks or months after birth, or not until two-and-a-half years of age. Because of its rarity, little is known about possible causative factors or conditions preceding or accompanying Autism.

Source and more information: Irish Society for Autism

Research Funders

• National Children’s Research Centre Our Lady’s Children’s Hospital Crumlin
• Health Research Board