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.

概括 神经发育障碍（NDDS）包括一组与异常大脑相关的疾病 发展。具有智力残疾（ID）的NDD，其特征是智力的重大局限性 运作和适应性行为会影响全球1％的人口，并带来重要的公共卫生 社会负担。触发NDD发作和 进展尚未完全理解。罕见的遗传变异已显示出在他们的 发展，特别是在那些本质上严重的NDD中。在过去的十年中，基因检测具有 成为对NDD的重要病因诊断测试，对疾病有很大影响 管理和治疗。然而，当前的基因检测的诊断率约为50％。由于技术 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。现在已经出现了新方法 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确定 复杂的结构基因组事件具有更准确性。 因此，我们假设NDD的病因涉及的大量遗传变异仍然存在 没有当前的测序技术未发现。必须表征基因组变体的光谱 在NDD中仍未发现以改善诊断检测方法。我们的目标是两个采用两个新成本 - 有效的技术，即光学基因组映射（OGM）和单管长片段读取测序 （STLFR），以确定50个具有严重NDD的遗传遗传学家族的潜在遗传原因 ID。以前使用标准的短阅读测序技术研究了这些家族 结果不确定。组合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，包括临床上显着的基因组变异。该项目是针对试点项目 更好地了解与异常神经发育相关的变体的基因组景观和 认识。由于技术的限制，我们目前对人类基因组的理解仍受到限制 这些结果将为大规模研究奠定基础，最终将改善遗传诊断 筛查和患者管理。