Exploring the Genomic Dark Matter of Neurodevelopmental Disorders

总结 神经发育障碍（NDD）包括一组与异常的大脑相关的疾病， 发展伴有智力残疾（ID）的NDD，其特点是智力严重受限 功能和适应行为影响全球1%的人口，并构成重大公共卫生问题 社会的负担。触发NDD发作的潜在神经元失调机制， 进展并不完全清楚。罕见的遗传变异已被证明在其 发展，特别是在那些性质严重的NDD。在过去的十年里，基因检测 成为NDD的重要病原学诊断试验，对疾病有相当大的影响 管理和治疗。然而，目前的基因检测的诊断率约为50%。由于技术 由于现代下一代测序技术的局限性，这些技术未能评估大部分的基因组序列。 基因组（2/3），缺失可能具有临床意义的关键区域。现在出现了新的方法 可以更好地评估这些区域（即基因组暗物质），可以访问重复区域并识别 复杂的结构基因组事件更准确。 因此，我们假设，参与NDD病因学的大部分遗传变异仍然存在， 目前的测序技术无法检测到。必须对基因组变异谱进行表征 在NDD中仍然未被检测到，以改进诊断检测方法。我们的目标是采用两种新的成本- 有效的技术，即光学基因组图谱（OGM）和单管长片段测序 （stLFR），以确定潜在的遗传原因，在50个遗传未解决的家庭与严重的NDD，包括 ID.这些家族先前使用标准短读段测序技术进行了研究， 不确定的结果。结合stLFR和OGM将提供基因组变异的增强概述 在难以诊断的病例中，包括临床上显著的基因组变异。该项目是一个试点项目， 为了更好地了解与异常神经发育相关的变异的基因组景观， 认知.由于技术的限制，我们目前对人类基因组的了解仍然有限， 这些结果将为更大规模的研究奠定基础，最终将改善遗传诊断。 筛查和患者管理。

SUMMARY Neurodevelopmental disorders (NDDs) comprise of a group of disorders associated with abnormal brain development. NDDs with intellectual disability (ID), characterized by significant limitations in intellectual functioning and adaptive behavior, affect 1% of the population globally and pose a significant public health burden on society. The underlying neuronal mechanisms of dysregulation that trigger NDD onset and progression are not fully understood. Rare genetic variants have been shown to play a key role in their development, especially in those NDDs which are severe in nature. During the last decade, genetic testing has emerged as an important etiological diagnostic test for NDDs with a considerable impact on disease management and treatment. Yet, current genetic testing has a diagnostic rate of ~ 50%. Due to technical limitations in modern next-generation sequencing techniques, these techniques fail to asses a large part of the genome (2/3rd), missing critical regions which may have clinical significance. New methods now have emerged that can assess these regions (i.e. the genomic dark matter) better, can access repetitive regions and identify complex structural genomic events with more accuracy. As such, we hypothesize that a large fraction of genetic variation involved in the etiology of NDDs remains undetected by current sequencing techniques. It is imperative to characterize the spectrum of genomic variants that remain undetected in NDDs to improve diagnostic detection methods. Our goal is two adopt two new cost- effective technologies, i.e. Optical Genome Mapping (OGM) and Single Tube Long Fragment Reads sequencing (stLFR), to identify the underlying genetic cause in 50 genetically unsolved families with severe NDDs including ID. These families were previously investigated using standard short-read sequencing technologies with inconclusive results. Combining both stLFR and OGM will provide an enhanced overview of genomic variation in difficult to diagnose cases, including clinically significant genomic variation. This project is a pilot project aimed to better understand the genomic landscape of variants associated with aberrant neurodevelopment and cognition. Our current understanding of the human genome is still limited due to restrictions in technologies, and these results will lay the foundation for a larger scale study which will eventually improve genetic diagnostic screening and patient management.