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Abstract：
Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. Clinical trials for FSHD are hindered by heterogeneous biomarkers poorly associated with clinical severity, requiring invasive muscle biopsy. Macroscopically, FSHD presents with slow fatty replacement of muscle, rapidly accelerated by inflammation. Mis-expression of the transcription factor DUX4 is currently accepted to underlie pathogenesis, and mechanisms including PAX7 target gene repression have been proposed. Here, we performed RNA-sequencing on MRI-guided inflamed and isogenic non-inflamed muscle biopsies from the same clinically characterized FSHD patients (n = 24), alongside isogenic peripheral blood mononucleated cells from a subset of patients (n = 13) and unaffected controls (n = 11). Multivariate models were employed to evaluate the clinical associations of five published FSHD transcriptomic biomarkers. We demonstrated that PAX7 target gene repression can discriminate control, inflamed and non-inflamed FSHD muscle independently of age and sex (P < 0.013), while the discriminatory power of DUX4 target genes was limited to distinguishing FSHD muscle from control. Importantly, the level of PAX7 target gene repression in non-inflamed muscle associated with clinical assessments of FSHD severity (P = 0.04). DUX4 target gene biomarkers in FSHD muscle showed associations with lower limb fat fraction and D4Z4 array length but not clinical assessment. Lastly, PAX7 target gene repression in FSHD muscle correlated with the level in isogenic peripheral blood mononucleated cells (P = 0.002). A refined PAX7 target gene biomarker comprising 143/601 PAX7 target genes computed in peripheral blood (the FSHD muscle-blood biomarker) associated with clinical severity in FSHD patients (P < 0.036). Our new circulating biomarker validates as a classifier of clinical severity in an independent data set of 54 FSHD patient and 29 matched control blood samples, with improved power in older patients (P = 0.03). In summary, we present the minimally invasive FSHD muscle-blood biomarker of FSHD clinical severity valid in patient muscle and blood, of potential use in routine disease monitoring and clinical trials.
摘要：
面肩肱型肌营养不良(FSHD)是一种普遍存在的,无法治愈的骨骼肌病.FSHD的临床试验受到与临床严重程度相关性差的异质性生物标志物的阻碍。需要进行侵入性肌肉活检.宏观上,FSHD表现为缓慢的肌肉脂肪替代，迅速加速炎症。转录因子DUX4的错误表达目前被认为是发病机理的基础，并提出了包括PAX7靶基因抑制在内的机制。这里,我们对来自相同临床特征的FSHD患者（n=24）的MRI引导的发炎和等基因非发炎肌肉活检进行了RNA测序，与来自一组患者（n=13）和未受影响的对照组（n=11）的等基因外周血单核细胞一起。采用多变量模型来评估五种已发表的FSHD转录组生物标志物的临床关联。我们证明了PAX7靶基因抑制可以区分控制，发炎和未发炎的FSHD肌肉与年龄和性别无关（P<0.013），而DUX4靶基因的辨别能力仅限于区分FSHD肌肉和对照。重要的是,非炎症肌肉中PAX7靶基因抑制水平与FSHD严重程度的临床评估相关(P=0.04)。FSHD肌肉中的DUX4靶基因生物标志物显示与下肢脂肪分数和D4Z4阵列长度相关，但与临床评估无关。最后,FSHD肌肉中的PAX7靶基因抑制与等基因外周血单核细胞中的水平相关（P=0.002）。一种精制的PAX7靶基因生物标志物,其包含在外周血中计算的143/601PAX7靶基因(FSHD肌肉-血液生物标志物),其与FSHD患者的临床严重程度相关(P〈0.036)。我们新的循环生物标志物在54名FSHD患者和29个匹配的对照血液样本的独立数据集中验证为临床严重程度的分类器。老年患者的功率改善（P=0.03）。总之,我们提出了在患者肌肉和血液中有效的FSHD临床严重程度的微创FSHD肌肉-血液生物标志物，在常规疾病监测和临床试验中的潜在用途。
