Accessible FSHD diagnostics through epigenetic analysis

通过表观遗传分析进行 FSHD 诊断

• 批准号: 10556422
• 负责人: Peter L Jones
• 金额: $ 19.4万
• 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 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10556422
• 关键词: 4q35; Address; Adult; Affect; Age; Biological Assay; Blood; CLIA certified; Child; Chromosomes; Chronic; Clinical; Clinical Trials; Collaborations; Communities; Complex; Computer software; Consumption; D4Z4; DNA; DNA Methylation; Development; Diagnosis; Diagnostic; Diagnostic tests; Dideoxy Chain Termination DNA Sequencing; Disease; Epigenetic Process; Ethnic Population; 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; autosome; clinical diagnosis; clinical outcome measures; cost; diagnostic biomarker; exome sequencing; genetic testing; male; meetings; member; next generation sequencing; novel diagnostics; patient stratification; permissiveness; 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.

概括 Facioscapulohumeral肌肉营养不良（FSHD）是常染色体显性肌肉疾病 这会影响各个年龄段的男性和女性。 FSHD被认为是第三大普遍的 肌肉营养不良（〜12：100,000成人）；但是，由于严重程度和并发症的变化 通过基因检测，许多人仍未诊断，并且患病率可能显着 更高。神经科医生对FSHD的临床诊断可能会因变异性而变得复杂 疾病表现，通常被误诊为肢体型肌肉营养不良或 简单的慢性损伤。使用基因特异性的神经肌肉疾病的标准基因检测 有针对性的测序面板甚至整个外显子组测序都无法识别FSHD1 （代表> 95％的FSHD病例），并且很容易错过FSHD2（<5％的病例）。下列的 临床诊断，基因检测很昂贵，许多人群无法使用。因此， 由于发病较晚，弱点的进展缓慢，高度可变的临床 许多FSHD表现，缺乏特定基因检测的访问或知识 个体一直未被诊断多年，这种疾病通过家庭流行，影响 几代人的多个成员。另外，由于当前的基因检测 FSHD昂贵，耗时，复杂，不完整且与标准遗传 针对其他神经肌肉疾病的测试技术，我们对 在世界许多地区以及某些种族和服务不足的人群中，FSHD甚至 在美国。为了满足这一需求，我们最近为所有形式开发了一项新颖的诊断测试 基于疾病基因座的表观遗传状况的FSHD。可以进行此分析 关于包括唾液在内的任何来源的基因组DNA以及几乎任何质量 任何年龄段的家庭成员和世界各地的人们都可以访问 服务不足的社区。在这里，我们将从低 - 转换当前的诊断协议 吞吐量一次用于高通量下一代测序协议。这个过渡 将大大降低测定的成本，并使它更适合获得Clia的批准。 此外，我们正在与移动FSHD研究和进行表观遗传分析合作 在所有250名参与者中。这些受试者将进行深入的临床评估并记录下来 自然历史将使我们能够确定疾病基因座的表观遗传特征是否可以 用作FSHD的预后生物标志物。