Systematic genomic characterization of cutaneous mosaic constitution (in individuals with intellectual disability) as the key to improved understanding of ID pathogenesis

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Intellectual disability (ID) is the most common developmental disorder worldwide. ID occurs either isolated (non-syndromic) or in combination with complex malformations, behavior deficits or distinct phenotypic changes (syndromic).Thus, despite of significant technological progress (whole exome sequencing (WES)/ NGS), current understanding of the etiopathogenesis of ID is incomplete. Research suggests that analysis of individuals by WES, predominantly performed on peripheral blood cells, led to the identification of a disease causing germline mutation in only 30% of by then molecularly unsolved patients with ID. This reflects the complexity of the underlying molecular signatures and the demand for new scientific strategies to gain more insights into ID biology. The evidence to date suggests that analysis of likely low-grade mosaicisms (LGM), which are not detectable by standard pipelines, as well as systematic genomic analysis of affected tissues, might be the key towards an improved understanding of ID pathophysiology. However, large systematic studies are missing and precise biological mechanisms are widely unexplored. In this context, skin is of high interest. Skin lesions often present in exceptional number, unusual location or bizarre configuration. These comprise a broad range of distinct skin manifestations, frequently including pigmentary changes (PC). At least 261 ID syndromes with PC are listed in the currently available LMD version. The high prevalence of PC in patients with ID points to shared underlying disease causing and specific molecular mechanisms. However, knowledge of the underlying basis is widely missing. The requested project aims for the first time to establish an in-depth understanding of the pathogenic causes of PC in patients with ID to shed further light on the biology of ID.By performing comprehensive molecular analyses comprising WES, RNA-sequencing and chip-based methylome approach of affected and matched surrounded healthy skin (fibroblasts, melanocytes) we aim to systematically characterize i) the mutational profile, ii) the gene expression profile and iii) the epigenetic profile. At once, trio-based WES as well as characterization of the transcriptome and methylome of peripheral blood cells shall be performed. Beside standard analysis pipelines, we aim to focus on the detection of LGM. Integrative analysis of genomic, proteomic and epigenetic profile of blood and skin findings will be performed to identify underlying, common and specific molecular pathways.For the requested project, 10 phenotypically well-defined samples, taken from the German MRNET consortium, are available. Trio-based WES of blood cells was already performed in all of them. Enlargement of the sample by further 10 patients (own genetic consultation, local Children`s Hospital, ERN-ITHACA) guarantees a sample of high-quality for the requested project.