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 面肩肱型肌营养不良症 (FSHD) 是一种常染色体显性肌肉疾病 影响所有年龄段的男性和女性。 FSHD 被认为是第三大流行病 肌营养不良症（~12:100,000 成人）；然而，由于严重程度和并发症的不同 通过基因检测，许多人仍未得到诊断，患病率可能会显着降低 更高。神经科医生对 FSHD 的临床诊断可能因以下因素的变异性而变得复杂： 疾病表现，经常被误诊为肢带型肌营养不良症或 单纯慢性损伤。使用特定基因对神经肌肉疾病进行标准基因检测 靶向测序面板甚至全外显子组测序均无法识别 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、基因检测价格昂贵，而且许多人群无法获得。因此， 由于发病较晚、无力进展缓慢、临床差异很大 许多 FSHD 缺乏对特定基因检测的了解或了解 个人多年来仍未得到诊断，并且该疾病在家庭中传播，影响 多个成员跨越几代人。此外，由于目前的基因检测 FSHD 昂贵、耗时、复杂、不完整且与标准遗传不相容 对于其他神经肌肉疾病的检测技术，我们对患病率知之甚少 FSHD 在世界许多地方以及某些种族和服务不足的人群中甚至 在美国境内。为了满足这一需求，我们最近开发了一种适用于所有形式的新型诊断测试 FSHD 基于疾病位点的表观遗传状态。可以执行此分析 任何来源（包括唾液）和几乎任何质量的基因组DNA，从而使其 任何年龄的家庭成员和世界各地的人们都可以广泛使用和访问 服务不足的社区。在这里，我们将当前的诊断协议从低位转换为 一次性使用高通量下一代测序方案。这种转变 将大大降低检测成本，并使其更容易获得 CLIA 批准。 此外，我们正在与 MOVE FSHD 研究合作并进行表观遗传学分析 所有 250 名参与者。这些受试者将进行深入的临床评估并记录在案 自然历史将使我们能够确定疾病位点的表观遗传特征是否可以 作为 FSHD 的预后生物标志物。