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The words «intellectual deficiency» (ID) are currently preferred to «mental retardation». The prevalence of intellectual deficiency among school-age children is estimated to be 3% (Roeleveld et al. 1997), making this condition a real public health concern. Moderate to severe ID (IQ <50) concern 0.5% of the population (Ropers 2010).

There are numerous causes for ID. The identification of the cause is essential for genetic counseling. In the absence of accurate diagnosis, it is not possible to eliminate the risk of recurrence and families choose not to have children or take the risk of recurrence in a future child. The precise knowledge of the diagnosis is a guidance element of care provided to the affected children. Finally, although there is still no specific treatment, the certainty of the diagnosis allows families to expect that research efforts will lead to a cure.

If environmental causes play a role in mild to moderate ID (especially maternal alcoholism in some countries), the genetic causes predominate in severe ID. Nonetheless, there is a high genetic heterogeneity. Pawlowski et col. reported that 50% of moderate to severe ID have a genetic origin. One usually distinguishes syndromic and non-syndromic forms. Syndromic forms are the forms where ID is associated with a group of recognizable symptoms on clinical examination (malformations, dysmorphic features), or upon additional examinations (brain imaging, metabolic screening). The term non-specific (or non syndromic) ID defines a situation in which dysmorphic features are absent, are mild, or do not correspond to a known syndrome. The intellectual deficiency is called "idiopathic" when it has no known cause, syndromic or not.

Visible chromosomal abnormalities on a standard karyotype represent 10% of the causes. The FISH technique (fluorescent in situ hybridization) or MLPA target one or more chromosomal regions to detect non-visible microrearrangements on the standard karyotype, particularly recurrent microdeletions. However, their use is limited by the fact that they require prior clinical orientation.

Comparative genomic microarray (array-CGH) hybridization identifies any quantitative DNA variation (by excess: duplication, or default: deletion) at a resolution of a few tens of base pairs to 1Mb in a single experiment, without prior clinical orientation. The acronym "CNV" (Copy Number Variation) is now used to refer to these chromosomal rearrangements having a size larger than 1kb, and resulting in gains or losses of chromosomal material. This "molecular karyotype" improves the diagnostic yield of 15 to 20% compared to karyotyping and FISH techniques and thus was quickly adopted as a first-line diagnostic tool by most labs. This strategy is effective both in terms of cost and response to the needs of families.

However, most CNVs are non-pathogenic. The interpretation of the result of an array-CGH analysis relies on bioinformatics, the query of databases of the CNVs present in healthy individuals, those CNVs whose pathogenicity has been demonstrated, the analysis of candidate genes contained in the region and the study of both parents. A CNV that occurred de novo (i.e. absent in both parents) is more likely to be pathogenic but this statement can be wrong and reaching a conclusion can be difficult when the CNV has not been described before.

The genes involved in monogenic forms of ID are far from being all known. The estimated number of genes varies according to the authors. The genes localized on the X chromosome are the better known and one hundred genes have already been identified to be responsible for a genetic form of ID (Ropers 2006). Some, based on the fact that 10-12% of the genes on the X chromosome may be involved in ID, estimated that there are 800-850 autosomal genes whose mutations will cause ID.

The first genes whose mutations are responsible for monogenic ID were identified by positional cloning. There were mainly localized on the X chromosome because of the existence of familial cases with a transmission through unaffected carrier females. The strategy of homozygosity mapping of consanguineous families has led to the description of several genes involved in non-syndromic ID. However, this approach proved to be very quickly limited because of genetic heterogeneity and the large number of sporadic syndromes. The chromosomal approach has played an important role in the identification of ID genes. Exceptional observations of balanced chromosomal translocations associated with known syndromes have allowed the identification of many new genes, both X-linked and autosomal.

High-throughput sequencing (next generation sequencing, NGS) is a technique allowing to analyze a large number of genes simultaneously. It therefore saves time at a lower cost than conventional sequencing. This technique applied to the entire coding sequences of the genome (exome sequencing) proved to be a very powerful tool for the identification of genes involved in rare genetic syndromes, particularly those with mutations at the origin of neurodevelopmental disorders (see Topper 2011). During the last few years, there was a significant acceleration in the identification of genes involved in ID. Globally, there are more than 200 genes whose mutations are responsible for ID. Many are involved in non-syndromic forms. The use of these high throughput sequencing techniques for diagnosis should improve the rate of success and the quality of service to patients and their families.

The identification of molecular mechanisms: a prerequisite for the development of therapeutic approaches.

Apart from the symptomatic treatment of associated manifestations (epilepsy, sleep disorders) and educational support, there is in most cases no treatment of the ID of neuro-developmental origin. In some common diseases whose molecular cause was identified several years ago, the creation of animal models and the development of basic research programs helped to describe the pathophysiological mechanisms and have lead to the first clinical trials (see Wetmore 2010). This is the case of Fragile X syndrome or Rett syndrome (see our work in this area by following this link). It appears that several of the proteins encoded by these genes are related at the functional level. The most numerous group is the group of proteins present in the synaptic compartment. Many of these proteins belong to known signaling pathways, and it is logical to hypothesize that pharmacological approaches could be offered to groups of patients with mutations in genes involved in common pathways. In this context, identifying the molecular cause of a child’s ID becomes a priority in conjunction with non-specific support, although no genetic counseling is sought.

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