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

皮肤嵌合体构成（智力障碍个体）的系统基因组表征是提高对 ID 发病机制了解的关键

• 批准号: 395095174
• 负责人: Professorin Dr. Silke Redler
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2018
• 资助国家: 德国
• 起止时间: 2017-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/395095174?language=en
• 关键词: Systematic; genomic; characterization; cutaneous; mosaic

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.

智力障碍(ID)是全世界最常见的发育障碍。ID要么是孤立的(非综合征)，要么是合并复杂的畸形、行为缺陷或明显的表型改变(综合征)。因此，尽管有重大的技术进步(整个外显子组测序/NGS)，但目前对ID的发病机制的了解是不完整的。研究表明，WES对个体的分析，主要是在外周血细胞上进行的，导致只有30%的当时在分子上尚未解决的ID患者中发现了一种导致胚系突变的疾病。这反映了潜在分子特征的复杂性，以及对新的科学策略的需求，以获得对ID生物学的更多洞察。到目前为止的证据表明，对标准管道无法检测到的可能的低级别嵌合体(LGM)的分析，以及对受影响组织的系统基因组分析，可能是改善对ID病理生理学理解的关键。然而，缺乏大规模的系统研究，精确的生物学机制也广泛未被探索。在这种情况下，皮肤引起了人们的高度关注。皮损通常以异常数量、不寻常的位置或奇怪的形态出现。这些症状包括一系列不同的皮肤表现，经常包括色素改变(PC)。目前可用的LMD版本中列出了至少261个与PC有关的ID综合征。PC在ID患者中的高患病率表明共同的潜在致病因素和特定的分子机制。然而，人们普遍缺乏对潜在基础的了解。这项请求的项目旨在首次深入了解ID患者中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(成纤维细胞、黑素细胞)进行全面的分子分析，包括WES、RNA测序和基于芯片的甲基组方法，我们的目标是系统地表征i)突变特征，ii)基因表达特征和iii)表观遗传学特征。同时，应进行基于三个组的WES以及外周血细胞转录组和甲基组的鉴定。除了标准的分析管道外，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、共同的和特殊的分子途径。对于所请求的项目，从德国MRNET财团获得了10个表型明确的样本。所有人都已经进行了基于TRIO的血细胞WES。进一步扩大样本10名患者(自己的遗传咨询、当地儿童医院、ERN-Ithaca)确保为所要求的项目提供高质量的样本。