Rare Chromosomal Aberrations that Contribute to Intellectual Disability Identified by TCD Researchers

Posted on: 29 September 2008

An international research collaboration between researchers in the US, Europe and Trinity College Dublin has identified rare chromosomal aberrations which are associated with a variety of developmental disorders in children including some cases of autism. The study’s findings which involved Dr Louise Gallagher, Clinical Senior Lecturer in Psychiatry and Professor of Psychiatry, Professor Michael Gill at TCD have just been published in the internationally renowned New England Journal of Medicine.

The study involved 5,218 patients, including patients recruited in Ireland. Patients were screened for submicroscopic mutations and identified similar mutations in a small region on chromosomal 1 called 1q.21 in approximately 34 cases. Chromosome 1 is one of the 23 pairs of chromosomes carrying genetic information in humans. Disruption of the chromosome in this region may be disrupting the expression of genes involved in brain development. Two thirds of the affected cases were missing one of the normal two copies of DNA at this region and 1/3 had an extra copy. The affected individuals had highly variable clinical features including mild or moderate intellectual disability, growth retardation, learning disabilities, seizures, autism, heart defects, other congenital abnormalities, cataracts, small head size, unusual facial features, hand deformities, or skeletal problems. The results were compared with 4,737 controls from the general population where no such chromosomal aberrations were found. Other work, also involving Trinity College Dublin, has found a connection between the same deletions on chromosome 1 and schizophrenia, and in abnormalities in the development of the reproductive tract.

The 1q21.1 deletions and duplications identified by the TCD researchers and international collaborators involve a sequence of about 1.3 million base pairs of DNA containing eight or nine genes. The genomic structure of the region 1q21.1 is extremely complex. There is still missing sequence in the current maps of the human genome in the 1q21.1 region, which might contain as yet unknown genes that may contribute to the differences in the types of developmental abnormalities that occur in cases with the abnormality.

Aberrations in the human genome, e.g. deletions and duplications are known to cause disease or increase disease susceptibility. Recent technological advances are enabling scientists to test large numbers of people to determine the presence or absence of submicroscopic imbalances in small sections of their chromosomes. Such aberrations would have remained undetected with older technologies. There is a strong interest in investigating these abnormalities, also known as ‘copy number variations’ in neuropsychiatric disorders, particularly autism and schizophrenia.

“We are actively pursuing this avenue of investigation in our sample of individuals with autism and have already seen several occurrences of these ‘copy number variations’ in affected individuals”, says Dr. Gallagher. “There is great hope in the autism community that these aberrations may help us to understand more about the biology of the condition and perhaps in the future to assist in the development of diagnostic tests and treatments.”

Autism is a neurodevelopmental disorder of childhood associated with impairments in communication, social interaction and the presence of rigid and repetitive behaviours. Autism is a broad spectrum of disorders ranging from the very severe to the mild and autism spectrum disorders collectively affect almost 0.5% of the population. They are associated with persistent and often severely disabling features. The knowledge about the underlying biology of autism is limited but genetic factors are strongly implicated and identifying risk genes is essential to understanding the underlying causes and to the development of improved treatments and interventions.

Dr. Louise Gallagher, Clinical Senior Lecturer in Psychiatry leads the Autism Genetics Group in TCD and is a Consultant Child and Adolescent Psychiatrist in the Adelaide and Meath Hospital incorporating the National Children’s Hospital, Tallaght and the Linn Dara Child and Adolescent Mental Health Service. The group is part of the Neuropsychiatric Genetics Group headed by Professor  Michael Gill, Professor of Psychiatry at TCD and St James’s Hospital. The group is involved in a number of international collaborations in autism genetics research including the Autism Genome Project (AGP) and The Autism Simplex Collection (TASC).  The Autism Genetics Group is supported by funding from the Health Research Board and Autism Speaks.

Notes to the Editor:
New England Journal of Medicine. Sept. 11 New England Journal of Medicine in an article entitled, “Recurrent Rearrangements of Chromosome 1q21.1 and Variable Pediatric Phenotypes.” and discussed in an accompanying editorial by David H. Ledbetter of Emory University in Atlanta.