The Erlangen MR Centre

Coordinator:    Prof. Dr. med. André Reis 
Institution: HumangenetischesInstitut, Universitätsklinikum Erlangen
Despite the achievements of genome research, the underlying cause in the majority of patients with intellectual disability (ID) remains unknown. Goal of the Erlangen MR centre was, in accordance with the network goals, the identification, validation and functional analysis of genes and proteins related to intellectual disability. The subproject made considerable progress over the entire funding period. More than 500 patients with developmental delay/intellectual disability were clinically evaluated in detail and data was entered into the central MRNET database. Using the well established molecular karyotyping platform in Erlangen, we analysed 376 patients from Erlangen and 204 patients recruited in subproject 8 (Essen) for copy number variants (CNVs). About 15 % of patients had possibly pathogenic CNVs. CNV analysis led to the characterization of a novel microdeletion syndrome on chromosome 5q14.3 and the identification of three novel ID genes (MEF2C, ARID1B and SMARCA2). Two further genes for ID with and without seizures were identified in cooperation with the subprojects in Essen, Heidelberg, Berlin and Prof. Kutsche in Hamburg (GRIN2A and GRIN2B). Using a linkage approache, we also successfully identified mutations in a novel gene encoding CCDC88C. In addition, about 90 Syrian families with autosomal recessive ID were analysed using positional cloning strategies and autozygosity mapping. In cooperation with international partners a new ID syndrome was identified, caused by mutations in any of the four members of the adaptor protein 4 complex, (AP4S1, AP4E1, AP4M1 and AP4B1). Further publications relating to genotype phenotype correlations of different microdeletions/microduplications are in preparation or already published (e.g. chromosome 16p11.2). A pilot study using next generation (exome) sequencing in 51 parent-child trios revealed that de novo point mutations and small insertions/deletions (indels) are a major cause of severe, sporadic non-syndromic ID with high locus heterogeneity. These findings altogether resulted in the publication of 18 peer reviewed research articles, so far.
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