Accessible FSHD diagnostics through epigenetic analysis

通过表观遗传分析进行 FSHD 诊断

• 批准号: 10391097
• 负责人: Peter L Jones
• 金额: $ 17.2万
• 依托单位: UNIVERSITY OF NEVADA RENO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10391097
• 关键词: 4q35; Address; Adult; Affect; Age; Biological Assay; Blood; CLIA certified; Child; Chromosomes; Chronic; Clinical; Clinical Trials; Communities; Complex; Computer software; Consumption; D4Z4; DNA; DNA Methylation; Development; Diagnosis; Diagnostic; Diagnostic tests; Dideoxy Chain Termination DNA Sequencing; Disease; Epigenetic Process; Ethnic group; Evaluation; Facioscapulohumeral Muscular Dystrophy; Family; Family member; Female; Generations; Genes; Genomic DNA; Individual; Injury; Knowledge; Laboratories; Life; Limb structure; Methodology; Modification; Molecular Weight; Motor; Muscular Dystrophies; Myopathy; Natural History; Neurologist; Neuromuscular Diseases; Outcome; Participant; Patients; Penetrance; Persons; Population; Populations at Risk; Prevalence; Prognostic Marker; Protocols documentation; Running; Saliva; Sampling; Severities; Site; Source; Symptoms; Techniques; Testing; Time; Underserved Population; Validation; Work; analysis pipeline; base; clinical diagnosis; clinical outcome measures; cost; diagnostic biomarker; exome sequencing; genetic testing; male; meetings; member; next generation sequencing; novel diagnostics; patient stratification; prognostic signature; prognostic value; research clinical testing; saliva sample; targeted sequencing; underserved community

SUMMARY Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant muscle disease that affects males and females of all ages. FSHD is thought to be the third most prevalent muscular dystrophy (~12:100,000 adults); however, due to variable severity and complications with genetic testing, many people remain undiagnosed and the prevalence may be significantly higher. The clinical diagnosis of FSHD by a neurologist can be complicated by the variability of disease presentation, and is often misdiagnosed as a limb-girdle type muscular dystrophy or a simple chronic injury. Standard genetic testing for neuromuscular disease using gene-specific targeted sequencing panels or even whole exome sequencing does not identify FSHD1 (representing >95% of FSHD cases) and can easily miss FSHD2 (<5% of cases). Following clinical diagnosis, genetic testing is expensive and not accessible to many populations. Thus, due to a combination of late onset, slow progression of weakness, highly variable clinical presentation, and lack of access to or knowledge of specific genetic testing, many FSHD individuals remain undiagnosed for years and the disease runs through families, affecting multiple members across several generations. In addition, since current genetic testing for FSHD is costly, time-consuming, complex, incomplete, and incompatible with standard genetic testing techniques for other neuromuscular diseases, we know very little about the prevalence of FSHD in many parts of the world as well as in certain ethnic and underserved populations even within the US. To address this need, we recently developed a novel diagnostic test for all forms of FSHD based on the epigenetic status of the disease locus. This analysis can be performed on genomic DNA from any source, including saliva, and of almost any quality, thereby making it widely available and accessible to family members of any age and people around the world in underserved communities. Here, we will convert the current diagnostic protocol from low- throughput single use to a high-throughput next-generation sequencing protocol. This transition will greatly reduce the cost of the assay and render it more amenable to meeting CLIA approval. In addition, we are collaborating with the MOVE FSHD study and performing epigenetic analysis on all 250 participants. These subjects will have in-depth clinical evaluations and documented natural histories which will allow us to determine if epigenetic profiles of the disease locus can serve as a prognostic biomarker for FSHD.

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