Association of 4qA-Specific Distal D4Z4 Hypomethylation With Disease Severity and Progression in Facioscapulohumeral Muscular Dystrophy.
Association of 4qA-Specific Distal D4Z4 Hypomethylation With Disease Severity and Progression in Facioscapulohumeral Muscular Dystrophy.
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DOI：
10.1212/wnl.0000000000207418
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发表时间：
2023-07-18
期刊：
影响因子：
9.9
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中科院分区：
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本研究的目的是检查 4qA 允许单倍型中最远端 D4Z4 重复单元 (RU) 的区域甲基化水平是否与 1 型面肩肱型肌营养不良症 (FSHD1) 的疾病严重程度和进展相关。这项为期 21 年的回顾性观察队列研究是在中国福建神经医学中心 (FNMC) 进行的。通过亚硫酸氢盐测序评估所有参与者最远端 D4Z4 RU（包括 10 个 CpG）的甲基化水平。根据甲基化百分比四分位数将 FSHD1 患者分为 4 组，包括 LM1（低甲基化）、LM2（低至中甲基化）、LM3（中至高甲基化）和最高甲基化 (HM) 水平。患者在基线和随访中接受了运动功能评估，重点关注下肢（LE）进展。使用FSHD临床评分（CS）、年龄校正临床严重程度量表（ACSS）和改良Rankin量表来评估运动功能。在所有 823 名基因证实的 FSHD1 患者中，10 个 CpG 的甲基化水平显着低于 341 名健康对照 (HC)。 CpG6 甲基化水平可以区分以下情况：（1）FSHD1 患者与 HC 患者； (2) 有症状的患者来自无症状/未受影响的患者； (3) LE受累患者与无LE受累患者相比，AUC（95% CI）分别为0.9684（0.9584-0.9785）、0.7417（0.6903-0.7931）和0.6386（0.5816-0.6956）。较低的 CpG6 甲基化水平与较高的 CS (r = -0.392)、较高的 ACSS (r = -0.432) 和较早的首次肌无力发病年龄 (r = 0.297) 相关。对于LM1、LM2、LM3和HM组，LE受累比例分别为52.9%、44.2%、36.9%和23.4%； LE 受累的发病年龄分别为 20、26.5、25 和 26.5 岁。 Cox 回归分析（针对性别、检查时年龄、D4Z4 RU 和 4qA/B 单倍型进行调整）显示，LM1、LM2 和 LM3 组（即甲基化水平较低的组）具有较高的独立行走丧失风险，HR (95% CI) 为 3.523 (1.565–7.930)、3.356分别为 (1.458–7.727) 和 2.956 (1.245–7.020)。 4q35 远端 D4Z4 低甲基化与疾病严重程度和下肢受累进展相关。
The objective of this study was to examine whether the regional methylation levels at the most distal D4Z4 repeat units (RU) in the 4qA-permissive haplotype were associated with disease severity and progression in facioscapulohumeral muscular dystrophy type 1 (FSHD1). This 21-year, retrospective, observational cohort study was conducted at the Fujian Neuromedical Center (FNMC) in China. Methylation levels of the most distal D4Z4 RU, including 10 CpGs, were assessed in all participants by bisulfite sequencing. Patients with FSHD1 were stratified into 4 groups based on methylation percentage quartiles, including LM1 (low methylation), LM2 (low to intermediate methylation), LM3 (intermediate to high methylation), and highest methylation (HM) levels. Patients received evaluations of motor function focusing on lower extremity (LE) progression at baseline and in follow-ups. FSHD clinical score (CS), age-corrected clinical severity scale (ACSS), and modified Rankin scale were used to assess motor function. The methylation levels of the 10 CpGs were significantly lower in all 823 patients with genetically confirmed FSHD1 than in 341 healthy controls (HCs). CpG6 methylation levels could distinguish the following: (1) patients with FSHD1 from HCs; (2) symptomatic from asymptomatic/unaffected patients; (3) patients with LE involvement from those without LE involvement, with AUCs (95% CI) of 0.9684 (0.9584–0.9785), 0.7417 (0.6903–0.7931), and 0.6386 (0.5816–0.6956), respectively. Lower CpG6 methylation levels were correlated with higher CS (r = -0.392), higher ACSS (r = -0.432), and earlier onset age of first-ever muscle weakness (r = 0.297). For the LM1, LM2, LM3, and HM groups, the respective proportions of LE involvement were 52.9%, 44.2%, 36.9%, and 23.4%; and onset ages of LE involvement were 20, 26.5, 25, and 26.5 years. Cox regression analysis—adjusted for sex, age at examination, D4Z4 RU, and 4qA/B haplotype—showed that the LM1, LM2, and LM3 groups (i.e., groups with lower methylation levels) had a higher risk of independent ambulation loss, with HRs (95% CI) of 3.523 (1.565–7.930), 3.356 (1.458–7.727), and 2.956 (1.245–7.020), respectively. 4q35 distal D4Z4 hypomethylation is correlated with disease severity and progression to lower extremity involvement.