NGFN-Plus
The Erlangen MR Centre
Coordinator: | Prof. Dr. med. André Reis | |
Institution: | HumangenetischesInstitut, Universitätsklinikum Erlangen | |
Homepage: | www.humangenetik.uk-erlangen.de |
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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