Genes and Mental Retardation

In the general population 2 to 3% of the children have a developmental delay or
mental retardation. Mental retardation can be caused by genetic or non-genetic
factors. For the majority of children with mental retardation it is currently
not possible to reveal the cause of the delay. In spite of intensive genetic
research over the last decades the genetic causes remains largely unknown as
well. An exception are the X-linked mental retardation disorders as for these
disorders large pedigrees are commonly available for genetic testing. Important
genetic causes of mental retardation are chromosomal aberrations. The most
frequent chromosomal aberration leading to mental retardation is a trisomy of
chromosome 21 causing the well recognisable Down syndrome. Till recently most
chromosome aberrations were identified by light-microscope analysis. Novel and
more accurate techniques have allowed the detection of smaller chromosome
aberrations not detectable by light microscope analysis so called
microdeletions or microduplications. This has led to the identification of
microdeletion syndromes that are causing mental retardation. Microdeletions
cause the loss of a copy of one or more genes (single in stead of the normal
two copies). So microdeletions will give information on the localisation of
genes involved in mental retardation.

The primary goal of this research project is the identification of genes
involved in causing mental retardation. These genes will be part of genetic
networks that play a role in normal brain development and function. With
up-to-date bioinformatic tools those networks will be explored and further
expanded leading to a better understanding of normal physiological processes in
the central neuronal system. Another goal is to get a better insight in the
frequency of these specific microdeletions in individuals with mental
retardation. In additional, new diagnostic tools will be developed in order to
improve the detection of genetic defects that lead to mental retardation. This
will improve the diagnosis of the patient with a mental handicap. A correct
diagnosis will improve the care of the child and will allow for better
counselling of the parents and other family members.

The study consist of the following parts:
1. The establishment of a phenotypic database of clinically well characterised
patients with a mental handicap (under code) en the collection of DNA samples
of an international cohort of patients with a mental handicap.
2. Identification of genomic disorders (microdeletions and microduplications)
using the following methods:
a. genome-wide deletion mapping using the 500 K SNP array
b. genome-wide homozygosity mapping and expression profiling using the Human
Exon 1.0 ST Array
3. The project will generate four datasets: phenotypes, genomic deletions and
duplications, homozygosity- and expression data. These datasets will be
subjected to an in-depth bioinformatics analysis to select candidate genes for
mental retardation. Candidate genes will be prioritized by in silico analysis
of genomic data and by text mining.
4. High throughput sequencing of candidate genes for mental retardation in
patients with an unknown cause of their mental handicap

Minimal