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

Silver-Russell综合征(SRS)属于少见疾病，但由于其临床异质性，常被认为是生长迟缓患者的鉴别诊断。相反，有越来越多的患者被临床诊断为SRS，但与其他生长发育迟缓疾病相关的分子障碍。SRS和其他先天性疾病之间的这些分子和临床重叠为相关分子因素的功能相互作用提供了证据。然而，这使得SRS及其相关疾病的基本分子改变的识别变得越来越困难。SRS是一种先天性印迹疾病。这些疾病的特征是相似的(外周)遗传障碍和重叠的临床特征。几项研究，包括申请人的研究，表明7号染色体和11p15.5号染色体上的印迹区域与疾病的病因有关。然而，更多的染色体区域也参与了SRS的病因学。针对这些区域的系统研究很少，而且只针对拷贝数变异。利用全外显子组测序技术(WES)对特发性SRS患者进行系统、全面和全基因组突变分析已成为可能。由于WES的方法和专业知识可以在亚琛的人类遗传学研究所获得，而且申请者小组概述了大量独特的患者队列，他们打算在特发性SRS家族的队列中进行WES。通过国家间的合作和网络，研究队列可以扩大，如果需要，突变的功能特征是可能的。在拟议的项目中，临床诊断为SRS但没有常见(EPI)遗传障碍的患者将通过WES进行分析，以确定导致SRS表型的遗传因素。因此，突变的光谱将被扩大，特别是病理机制将被揭示。可以预期，将实现对功能相互作用和网络的进一步洞察，正如在SRS中检测到的一些(Epi)突变(例如，IGF轴、印记基因网络IGN)所显示的那样。到目前为止，SRS患者在临床诊断没有得到分子证实的情况下，经历了一段诊断和治疗的奥德赛。事实上，根据疾病的分子原因，一些治疗可能是不充分的或禁忌的。因此，该项目的另一个目标是改进现有的诊断算法，同时考虑在小于胎龄的新生儿和SRS相关特征中使用分子测试。这种早期诊断将支持鉴别诊断，并将有助于更直接的治疗。

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.