Exploring the Genomic Dark Matter of Neurodevelopmental Disorders

探索神经发育障碍的基因组暗物质

基本信息

批准号：
10452910
负责人：
Isabelle Veerle Suzanne Schrauwen
金额：
$ 24.38万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452910
关键词：
Adaptive Behaviors Adopted Affect Bar Codes Child Clinical Cognition Complex Counseling DNA Data 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 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

项目摘要

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 (NDD) 包括一组与大脑异常相关的疾病发展。患有智力障碍 (ID) 的 NDD，其特征是智力严重受限功能和适应性行为，影响全球 1% 的人口，并对公共卫生构成重大影响社会负担。引发 NDD 发作的潜在神经元调节失调机制进展尚不完全清楚。罕见的遗传变异已被证明在其发生中发挥着关键作用发展，尤其是那些性质严重的 NDD。在过去的十年里，基因检测已经已成为 NDD 的重要病因诊断测试，对疾病具有相当大的影响管理和治疗。然而，目前的基因检测诊断率约为 50%。由于技术原因由于现代下一代测序技术的局限性，这些技术无法评估大部分基因组（2/3），缺失可能具有临床意义的关键区域。现在新方法已经出现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加准确。因此，我们假设 NDD 病因中涉及的很大一部分遗传变异仍然存在目前的测序技术无法检测到。必须表征基因组变异的范围 NDD 中仍未检测到的缺陷，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，即光学基因组图谱（OGM）和单管长片段读取测序 (stLFR)，旨在确定 50 个患有严重 NDD 的遗传未解决家庭的潜在遗传原因，包括 ID。之前使用标准短读长测序技术对这些家族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，包括临床上显着的基因组变异。该项目是一个试点项目，旨在更好地了解与异常神经发育相关的变异的基因组景观认识。由于技术的限制，我们目前对人类基因组的了解仍然有限，并且这些结果将为更大规模的研究奠定基础，最终改善基因诊断筛查和患者管理。