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A new diagnostic tool for rapid detection and characterization of REPEAT SEQUENCES in inherited diseases

一种新的诊断工具，用于快速检测和表征遗传性疾病中的重复序列

基本信息

批准号：
10682387
负责人：
Jason C Reed
金额：
$ 20.33万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
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：
2022-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10682387
关键词：
Affect Age of Onset Ataxia Atomic Force Microscopy Bar Codes Benchmarking Bioinformatics CGG repeat Capillary Electrophoresis Child Clinic Clinical Complex Coupled DNA DNA Sequence Alteration Decision Making Detection Development Diagnosis Diagnostic Disease Disease Management Early Diagnosis Elderly Equilibrium Etiology FMR1 FXTAS Family Family Planning Family member Fragile X Syndrome Generations Genes Genetic Genetic Anticipation Genetic Counseling Genetic Phenomena Genetic Risk Genome Genomic DNA Genomics Goals Healthcare Hereditary Disease Hospitals Individual Inherited Insurance Carriers Label Lead Length Lesion MJD1 protein Managed Care Measures Medical Medical Genetics Meiosis Memory Disorders Methodology Methods Molecular Monitor Mood Disorders Movement Mutation Nature Patient Monitoring Patients Performance Persons Phenotype Physicians Polymerase Polymerase Chain Reaction Procedures Process Product Labeling Prognosis Relative Risks Risk Sampling Severities Skeletal Muscle Southern Blotting Speed Spinocerebellar Ataxias Stretching Symptoms System Techniques Technology Testing Time Tremor Trinucleotide Repeat Expansion Trinucleotide Repeats United States Variant Walking base biobank clinically relevant cost design diagnostic tool genetic analysis genetic disorder diagnosis genetic testing health care economics improved member multiplex assay multiplex detection mutant nanoparticle nanopore nervous system disorder new therapeutic target next generation sequencing non-genetic novel diagnostics novel strategies offspring patient stratification rapid detection risk stratification screening sequencing platform success targeted treatment tool virtual

项目摘要

=. PROJECT SUMMARY …... Ataxia is a discoordination of voluntary muscle movement and can be seen as the primary symptom of multiple disorders including genetic and non-genetic etiologies. Several genes are implicated in causing Spinocerebellar ataxia through trinucleotide repeat expansions (TREs) and are thought to affect between 1.5 to 4 per 10,000 people globally. Similar trinucleotide repeat expansions in the FMR1 gene, including potentially symptomatic premutations, can be found in around 1 in 300 people in the United States. Detection of repeat expansion disorders in a family are important for understanding genetic risks and early detection in at risk members, especially since unstable repeat expansions lead to the phenomenon of genetic anticipation, where symptoms can present earlier or more severely across generations. Additionally, several recent studies have suggested development of targeted therapies specifically targeting expanded repeats as a novel therapeutic target. As such, earlier and rapid detection of these disorders is crucial for advancing their medical management. Traditionally, short TRE targets are assessed via repeat-primed PCR (PR-PCR) and capillary electrophoresis, while longer mutants are confirmed via Southern blotting. This is clinically important, especially where repeat lengths outside of the range quantifiable by PR-PCR are diagnostically relevant. Testing for most TRE genes remains difficult for short read sequencing platforms, where repeat tract lengths exceed average read length (~100 bp for Illumina systems). Long-read sequencing technologies like PacBio and Oxford Nanopore have shown success in measuring TREs, however a combination of high costs, large quantities of DNA input, complex bioinformatics, problems determining repeat region boundaries, and high error rates makes them an unlikely solution for widespread screening in their current state We developed a solution, PRECYSE, based on high-speed atomic force microscopy (HSAFM) paired with unique ‘nanoparticle barcoding’ that can potentially characterize complex structural variants for numerous ataxia conditions simultaneously at much lower cost than possible with next generation sequencing (NGS) sequencing and other emerging approaches. This extremely sensitive technique can be conducted without using polymerase chain reaction (PCR) and can span a very wide range of possible target sizes, thereby allowing extension to virtually unlimited molecular lengths. Our hypothesis is that this technology can be easily adapted to multiplexed detection of TRE targets of practically any length. If successfully developed, our new approach will change the way clinicians identify, understand, and monitor changes in the genome caused by trinucleotide repeat expansion diseases through multiplexed panels. At the end of this R21 project, we will have a platform for multiplexed genomic analysis that successfully purifies and detects trinucleotide repeat targets. However, a follow-on larger scale (50-60 samples) planned R01 project will provide statistical significance and further refine the methodology.

=。项目总结......