It has long been known, but without explanation, that there is a high variability in intellectual abilities among individuals living with Down syndrome. The project "Transcriptome-Trisomy 21" was initiated under the direction of Dr. Andre Magarbane of the Jerome Lejeune Institute to identify the unique genomic information of individuals with trisomy 21 to determine the cause, or causes, that explain this variability.

The human genome is made up of a long winding molecule that contains all the genetic information, or DNA, needed to build and maintain the human organism. For this activity to be carried out, a so-called “transcript” must be written that provides a set of instructions for the manufacturing (encoding) of proteins and enzymes by the genes that reside on each chromosome on the genome. This transcript is written onto corresponding molecules called RNA. A “transcriptome” is a collection of all of these instructions in a given cell, and it is unique to each individual and changes in response to varying external, or epigenetic factors. By analyzing this transcriptome, researchers can understand how and when each gene is turned on and off. By comparing the transcriptomes of different individuals, researchers can come to a better understanding of how the same genes can be expressed differently in each person. In the case of intellectual disability, studying transcriptomes might answer the question of why there is variability of intellectual ability, and which genes are responsible.

The Transcriptome – Trisomy 21 program was designed to identify the gene expression profile, or the transcriptome, of individual patients, and to quantify gene transcripts from patients with trisomy 21 as a expression of the degree of their cognitive impairment, comparing them to typically developing individuals.

Using biomarkers in blood, the goal is to to characterize specific populations of patients, which might then lead to the targeted development of innovative new medicines, and ways of patient monitoring. In other words, the goal is to be able to tailor future treatments to specific patient needs, and to promote the use of new potential therapeutic approaches.

Approach

Our approach searched for genes expressed in two groups of adult patients (aged 18-40 years) considered intellectually "high" and "low" functioning according to performance on standard tests of cognitive ability. A total of 80 genes were selected after analysis of the transcriptome.

Two of the HLA genes, HLA DQA1 and HLA DRB1, showed very significant differences in their expression between the 2 groups. The HLA system has been described as being a risk factor for certain diseases in individuals with trisomy 21, such as celiac disease. (Note: HLA genes are genes in humans that are responsible for regulating the immune system)

The pattern of expression of other genes was also analyzed, for example the enzyme CBS (cystathionine β-synthase), and the APP (Amyloid Precursor Protein) gene, both of which were overexpressed in the low IQ group. It is interesting to note that an excess of APP is responsible for the accumulation in the brain of amyloid plaques that are characteristic of Alzheimer's disease and often lead to dementia.

This study has allowed us to better understand previous observations such as those made in 1993 by Drs. Lejeune and Marie Peeters on some of their patients with trisomy 21 who had other neurological disorders. We analyzed the GART gene that encodes an enzyme that plays a key role in the biosynthesis of purine bases.

Future of the Project

To our knowledge, no link had been established to date between intellectual impairment in trisomy 21 and expression of genes such as those belonging to the HLA system. The next task is to explore the current findings in order to better understand how and why the genes HLA-DQA1 and HLA-DRB1 are biomarkers that can predict a difference in IQ in patients with trisomy 21.

Reference:

Intellectual disability of trisomy 21: differences in gene expression in a case series of patients with lower and higher IQ. André Mégarbané Florian Noguier, Samantha Stora, Laurent Manchon, Clotilde Mircher Roman Bruno, Nathalie Dorison, Fabien Pierrat, Marie-Odile Rethore, Bernadette Trentin, Aimé Ravel, Marine Morent, Gerard Lefranc, and David Thornton. . European Journal of Human Genetics (Feb 2013).