Exploring the Genomic Dark Matter of Neurodevelopmental Disorders

探索神经发育障碍的基因组暗物质

• 批准号: 10615832
• 负责人: Isabelle Veerle Suzanne Schrauwen
• 金额: $ 20.31万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615832
• 关键词: Adaptive Behaviors; Adopted; Affect; Bar Codes; Child; Clinical; Cognition; Complex; Counseling; DNA; Defect; Detection; Development; Diagnosis; Diagnostic; Diagnostic Procedure; Diagnostic tests; Disease; Disease Management; Etiology; Evaluation; Event; Family; Foundations; Future; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Genome Mappings; Genomic Segment; Genomic approach; Genomics; Goals; Human Genome; Impairment; Individual; Inheritance Patterns; Intellectual functioning disability; Investigation; Knowledge; Maps; Methods; Modernization; Molecular; Morbidity - disease rate; Nature; Neurodevelopmental Disorder; Neurons; Onset of illness; Optics; Parents; Pathogenicity; Patients; Pilot Projects; Play; Population; Prevalence; Prevention; Prognosis; Public Health; Quality of life; Recurrence; Repetitive Sequence; Site; Societies; Subgroup; Symptoms; Techniques; Technology; Testing; Therapeutic Intervention; Tube; Validation; Variant; brain abnormalities; burden of illness; care costs; causal variant; clinically significant; comorbidity; cost effective; dark matter; data integration; detection method; diagnostic screening; diagnostic tool; exome; genetic testing; genetic variant; genome sequencing; genomic variation; improved; innovation; innovative technologies; life time cost; neurodevelopment; next generation sequencing; novel; offspring; rare variant; reconstruction; therapeutic development

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.

摘要 神经发育障碍(NDDS)由一组与异常大脑相关的疾病组成 发展。有智力残疾(ID)的非智力发展障碍，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，并构成重大公共健康 给社会带来负担。触发NDD发生和发展的调节失调的潜在神经机制 进展还没有完全被理解。罕见的基因变异已被证明在它们的 发展，特别是在那些性质严重的国家发展中。在过去的十年里，基因检测已经 作为一种重要的NDDS病因学诊断试验，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%。由于技术原因 现代下一代测序技术的局限性，这些技术无法评估很大一部分 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 更准确的复杂结构基因组事件。 因此，我们假设与NDDS病因学有关的大部分遗传变异仍然存在。 未被当前测序技术检测到的。刻画基因组变异的光谱是当务之急。 在NDDS中仍未检测到的，以改进诊断检测方法。我们的目标是两个采用两个新的成本- 有效的技术，即光学基因组作图(OGM)和单管长片段阅读序列测序 (StLFR)，在50个患有严重NDD的遗传未解决的家庭中确定潜在的遗传原因，包括 这些家系之前使用标准的短读测序技术进行了研究 没有定论的结果。将stLFR和OGM结合起来将提供对基因组变异的更好的概述 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，旨在 为了更好地了解与神经发育异常和基因变异相关的基因组图谱 认知力。由于技术的限制，我们目前对人类基因组的了解仍然有限，而且 这些结果将为最终改进基因诊断的更大规模的研究奠定基础 筛查和病人管理。