Accessible FSHD diagnostics through epigenetic analysis

总结 面肩肱型肌营养不良症是一种常染色体显性遗传性肌肉疾病 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（约12：100，000成人）;然而，由于不同的严重程度和并发症， 通过基因检测，许多人仍然没有被诊断出来，患病率可能会显着增加。 高神经科医生对FSHD的临床诊断可能会因以下因素的变化而复杂化： 疾病的表现，并经常被误诊为肢带型肌营养不良症或 简单的慢性损伤神经肌肉疾病的标准基因检测使用基因特异性 靶向测序板或甚至整个外显子组测序不能鉴定FSHD 1 （代表>95%的FSHD病例）并且可以容易地错过FSHD 2（<5%的病例）。以下 临床诊断，基因检测是昂贵的，许多人无法获得。因此，在本发明中， 由于迟发性、缓慢进展的虚弱、高度可变的临床 介绍，以及缺乏获得或特定基因检测的知识，许多FSHD 个人多年未被诊断，疾病通过家庭传播， 几代人中的多个成员。此外，由于目前的基因检测 FSHD是昂贵的、耗时的、复杂的、不完整的，并且与标准遗传学不相容。 其他神经肌肉疾病的测试技术，我们对患病率知之甚少， 在世界许多地方，以及某些种族和服务不足的人群中， 在美国境内。为了满足这一需求，我们最近开发了一种新的诊断测试， FSHD基于疾病位点的表观遗传状态。该分析可以通过 来自任何来源的基因组DNA，包括唾液，几乎任何质量，从而使其 广泛提供给任何年龄的家庭成员和世界各地的人们， 服务不足的社区。在这里，我们将把当前的诊断协议从低- 从单次使用的高通量到高通量的下一代测序方案。这一过渡 将大大降低测定的成本，并使其更易于满足CLIA批准。 此外，我们正在与MOVE FSHD研究合作，并进行表观遗传分析。 250名参与者。这些受试者将接受深入的临床评价，并记录 自然史，这将使我们能够确定疾病位点的表观遗传谱是否可以 作为FSHD的预后生物标志物。

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.