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Identification of molecular causes of human growth retardation in patients with features of Silver-Russell syndrome

鉴定具有 Silver-Russell 综合征特征的人类生长迟缓的分子原因

基本信息

批准号：
350540879
负责人：
Professor Dr. Thomas Eggermann, Ph.D.
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：
2017
资助国家：
德国
起止时间：
2016-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/350540879?language=en
关键词：
Identification molecular causes human growth

项目摘要

Silver-Russell syndrome (SRS) belongs to the group of rare diseases, but due to its clinical heterogeneity it is often considered as differential diagnosis in patients with growth retardation. Vice versa, there is a growing number of reports on patients with the clinical diagnosis of SRS, but with molecular disturbances associated with other growth retardation disorders. These molecular and clinical overlaps between SRS and other congenital diseases provide evidence for a functional interaction of the involved molecular factors. However, they make the identification of the basic molecular alterations in SRS and related disorders more and more difficult.SRS is one of the congenital imprinting disorders. These diseases are characterized by similar (epi)genetic disturbances and overlapping clinical features. Several studies, including those of the applicant, indicate that the imprinted region on chromosomes 7 and 11p15.5 contribute to the etiology of the disorder. However, also further chromosomal regions are involved in the pathoetiology of SRS. Systematic studies aiming on these regions are rare and target only copy number variations. With whole exome sequencing (WES), the systematic, comprehensive and genomewide mutation analysis in idiopathic SRS patients is possible now. As the method and the expertise for WES is available at the Institute of Human Genetics in Aachen, and the group of the applicant overviews a large and unique cohort of patients, they intend to perform WES in a cohort of idiopathic SRS families. By (inter)national cooperations and networks, the study cohort can be enlarged, and functional characterizations of mutations is possible if needed.In the proposed project, patients clinically diagnosed as SRS but without one of common (epi)genetic disturbances will be analysed by WES to identify genetic factors contributing to the SRS phenotype. As a result, the spectrum of mutations will be enlarged, and particularly the pathomechanisms will be enlightened. It can be expected that further insights in functional interactions and networks will be achieved, as already shown for some of the (epi)mutations detected in SRS (e.g. IGF axis, imprinted genes network IGN). Up to now, SRS patients without a molecular confirmation of their clinical diagnosis undergo an odyssey of diagnostics and treatment. In fact, some of the treatments can be insufficient or contraindicated, depending on the molecular cause of the disease. Therefore, a further aim of the project is the improvement of the already existing diagnostic algorithm, also by considering the use of molecular tests in newborn born small for gestational age and SRS related features. This early diagnosis will support the differential diagnostics and will contribute to a more directed therapy.

银罗素综合征（Silver-Russell syndrome， SRS）属于罕见病，但由于其临床异质性，常被视为生长发育迟缓患者的鉴别诊断。反之亦然，也有越来越多的患者临床诊断为SRS，但存在与其他生长发育迟缓障碍相关的分子紊乱的报道。SRS与其他先天性疾病之间的分子和临床重叠为相关分子因子的功能相互作用提供了证据。然而，它们使得识别SRS及相关疾病的基本分子改变变得越来越困难。SRS是一种先天性印记疾病。这些疾病的特点是相似的遗传紊乱和重叠的临床特征。包括申请人的研究在内的几项研究表明，染色体7和11p15.5上的印迹区域与该疾病的病因有关。然而，其他染色体区域也参与了SRS的病理过程。针对这些区域的系统研究很少，而且只针对拷贝数的变化。利用全外显子组测序（WES），可以对特发性SRS患者进行系统、全面、全基因组的突变分析。由于亚琛人类遗传学研究所提供了WES的方法和专业知识，并且申请人小组概述了一个庞大而独特的患者队列，他们打算在特发性SRS家族队列中进行WES。通过（国际）国家合作和网络，研究队列可以扩大，如果需要，突变的功能特征是可能的。在该项目中，临床诊断为SRS但没有常见遗传障碍（epi）之一的患者将通过WES分析，以确定导致SRS表型的遗传因素。因此，突变的范围将扩大，特别是病理机制将得到启示。可以预期，对功能相互作用和网络的进一步了解将会实现，正如已经在SRS中检测到的一些（epi）突变（例如IGF轴，印迹基因网络IGN）所示。到目前为止，SRS患者在没有临床诊断的分子证实的情况下，经历了漫长的诊断和治疗过程。事实上，根据疾病的分子原因，一些治疗可能是不足的或禁忌的。因此，该项目的另一个目标是改进现有的诊断算法，同时考虑对胎龄较小的新生儿和SRS相关特征进行分子检测。这种早期诊断将有助于鉴别诊断，并有助于更有针对性的治疗。