German Mental Retardation Network ("MRNET")

Coordinator:    Prof. Dr. André Reis
Institution: Friedrich-Alexander-Universität Erlangen-Nürnberg
Mental retardation (MR), meanwhile referred to as intellectual disability (ID), has a prevalence of about 2% in the general population and is a major unresolved problem in health care. Although most cases are caused by genetic defects, only few causative genes were known. For this reason, the major goal of the German Mental Retardation Network (MRNET) project was the systematic identification of genes involved in ID and the functional investigation of respective proteins. Within MRNET a medical genetic approach was combined with systematic genome analysis.
To date almost 3000 patients were recruited and received a standardized clinical evaluation based on an international language for phenotype description (ontology). Sporadic as well as familial cases were included and several strategies for gene identification applied. Disease causing submicroscopic chromosomal aberrations (copy number variants, CNVs) were detected in about 15% of cases using state of the art micro-array based technologies. Patients with similar phenotypes to those with the CNV were screened for point mutations in candidate genes from the respective genomic region. In familial cases we studied cosegregation of genetic markers with the disease (linkage analysis) to likewise reveal candidate genes from linked regions. Furthermore, some patients were subject to comprehensive sequencing of the entire coding sequence (exome) with next-generation sequencing technologies. Finally, candidate genes and their respective signalling pathways were functionally investigated using cellular assays and animal models.
Overall, the coordinated research within and collaboration between MRNET members allowed identification of some 80 genes for intellectual disability. A total of 55 publications in international peer reviewed journals were published. Two publications can be highlighted, one in the journal Nature (Nadjmabadi et al. 2011), in which 50 novel genes for autosomal recessive ID were described and a paper in the prestigious medical journal The Lancet (Rauch et al. 2012), in which a comprehensive analysis using next generation sequencing of the genetic architecture of severe sporadic ID was reported.
Furthermore, intensive outreach activities were performed. A web page and a newsletter provided a forum for communication with affected families and the general public and to disseminate the work of the project. Also the media including journals like „Die Zeit“ and „Nature“ covered repeatedly the work of MRNET. An international scientific meeting in 2010 in Erlangen, organised in conjunction with the German National Science Academy Leopoldina, contributed significantly to the visibility of MRNET within the scientific community.
In summary, the MRNET results substantially extended the diagnostic options in affected patients and contributed to a better understanding of disease aetiology as well as the underlying pathomechanisms. It is now already possible to determine the genetic cause in over 60% of patients with ID. A further important finding was that the majority of mutations found in the patients represent new (de novo) mutations. Therefore, these parents have only a slightly increased recurrence risk.

Latest results can be found in detail in the descriptions of the subprojects

Molecular Karyogram. Schematic representation of chromosomes of a female patient with intellectual disability. Regions with loss (red arrows) or gain (blue arrows) of genetic material detected by molecular karyotyping are shown on the left side of the diagram.
As an example, intensity scores of markers at chromosome 11 are shown on the right side of the diagram. A downward deviation from the base line indicates a loss (deletion) of an 11 Million basepair region, affecting 58 genes partially expressed in brain. This is most probably the cause of the intellectual disability in this individual. Both parents do not carry this deletion, thus representing most likely a de novo mutation.

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