Next generation sequencing and imprinting disorders: Current applications and future perspectives: Lessons from Silver-Russell syndrome
Next generation sequencing and imprinting disorders: Current applications and future perspectives: Lessons from Silver-Russell syndrome
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DOI：
10.1016/j.mcp.2018.12.007
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发表时间：
2019-04-01
影响因子：
3.3
通讯作者：
Eggermann, Thomas
中科院分区：
文献类型：
--
作者：
Neuheuser, Lea;Meyer, Robert;Eggermann, Thomas
印迹障碍是一组具有重叠表型的罕见疾病，其与相似的分子变化相关并影响印迹染色体区域。临床特征主要发生在产前或儿童期，但对健康有严重的终身影响。由于其临床和分子异质性，印迹疾病的诊断往往是具有挑战性的，需要测试广泛的基因组变异和印迹基因座的异常甲基化（表突变）。大量的患者可疑的印迹疾病仍然没有分子确认，在这些情况下，鉴别诊断必须考虑。事实上，在临床特征提示为印迹疾病的患者中，分子病因的精确鉴定对于临床管理以及遗传咨询都是相关的。因此，必须采用全面的测试方法。基于下一代测序（NGS）的研究表明，该技术是提高诊断效率的有价值的工具，特别是在具有广泛鉴别诊断的实体中。此外，不同NGS方法的发展允许对印迹区域的功能、结构、相互作用和调控有新的见解。基于常规银罗素综合征检测的患者的大队列，在本报告中证明了首次试验测试在印迹疾病中的适当性和局限性，但也阐明了基因组NGS方法用于诊断和研究的机会。最后，将讨论精确分子诊断对患者个性化管理和家庭遗传咨询的意义。
Imprinting Disorders are a group of rare diseases with overlapping phenotypes which are associated with similar molecular changes and affect imprinted chromosomal regions. Clinical features mainly occur prenatally or in childhood, but have a severe lifelong impact on health. Due to their clinical and molecular heterogeneity, the diagnosis of imprinting disorders is often challenging and requires testing of a broad spectrum of genomic variants and aberrant methylation of imprinted loci (epimutations). A significant number of patients suspicious for imprinting disorders remain without a molecular confirmation, and in these cases differential diagnoses have to be considered. In fact, in patients with clinical features suggestive for imprinting disorders, the precise identification of the molecular cause is relevant for both clinical management as well as for genetic counselling. Thus, a comprehensive testing approach has to be applied. Next generation sequencing (NGS) based studies show that this technique is a valuable tool to improve the diagnostic efficiency particularly in entities with broad differential diagnoses. Furthermore, the development of diverse NGS approaches allows new insights in the function of imprinted regions, their structures, interactions and regulation. Based on a large cohort of patients referred for routine Silver Russel syndrome testing, the appropriateness and limitations of first trial tests in imprinting disorders are demonstrated in this report, but the chances of genomic NGS approaches for diagnostics and research are elucidated as well. Finally, the significance of the precise molecular diagnosis for the personalized management of the patient, and genetic counselling of the family will be discussed.