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

智力残疾（ID）是世界上最常见的发育障碍。ID可以单独发生（非综合征），也可以与复杂畸形、行为缺陷或明显的表型改变（综合征）结合发生。因此，尽管有显著的技术进步（全外显子组测序（WES）/ NGS），但目前对ID的发病机制的理解是不完整的。研究表明，通过WES对个体进行分析，主要是对外周血细胞进行分析，导致在当时分子上未解决的ID患者中仅30%的疾病引起生殖系突变的鉴定。这反映了潜在分子特征的复杂性以及对新科学策略的需求，以获得对ID生物学的更多见解。迄今为止的证据表明，分析可能的低级嵌合体（LGM），这是无法检测到的标准管道，以及系统的基因组分析受影响的组织，可能是关键，以提高对ID的病理生理学的理解。然而，缺乏大规模的系统研究，精确的生物学机制也未被广泛探索。在这种情况下，皮肤受到高度关注。皮肤病变往往存在于特殊的数量，不寻常的位置或奇怪的配置。这些包括广泛的不同皮肤表现，通常包括色素性变化（PC）。在当前可用的LMD版本中列出了至少261个具有PC的ID综合征。ID患者中PC的高患病率表明共同的潜在疾病病因和特定的分子机制。然而，人们普遍缺乏对基本原理的了解。申请的项目旨在首次深入了解ID患者PC的致病原因，以进一步阐明ID的生物学。通过对受影响和匹配的周围健康皮肤进行全面的分子分析，包括WES，RNA测序和基于芯片的甲基化方法（成纤维细胞，黑素细胞），我们旨在系统地表征i）突变谱，ii）基因表达谱和iii）表观遗传谱。应立即进行基于trio的WES以及外周血细胞转录组和甲基化组的表征。除了标准分析管道外，我们的目标是专注于LGM的检测。将对血液和皮肤的基因组、蛋白质组和表观遗传学特征进行综合分析，以确定潜在的、共同的和特异的分子途径。对于所请求的项目，可获得来自德国MRNET联盟的10个表型明确的样本。已经在所有患者中进行了基于三重的血细胞WES。由另外10名患者（自己的遗传咨询，当地儿童医院，ERN-EARNACA）对样本进行鉴定，保证了所需项目的高质量样本。

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.