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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：
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
项目类别：
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

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.

总结