RFC1纯合AAGGG重复扩增在特发性周围神经病中常见
本研究对美国788例特发性周围神经病（iPN）患者进行全基因组测序并以PCR验证，开发了检测RFC1重复扩增的整合分析流程，与重复引物PCR验证一致性达97.2%。双等位RFC1扩增在iPN中占2.3%（18/788），显著高于对照的1/778（Fisher精确P=7×10⁻⁵），在纯感觉神经病中达6.9%。
要点
- 双等位RFC1 AAGGG扩增见于2.3%的iPN患者，对照仅1/778，差异显著。
- 纯感觉神经病中双等位扩增频率最高（6.9%），运动神经受累不应排除RFC1筛查。
- 单等位扩增在iPN中频率略高（9.1% vs 7.2%）但未达统计学显著性（P=0.17）。
核心结论
- 双等位（纯合）RFC1 AAGGG重复扩增是特发性周围神经病的致病因素之一。
- 单等位扩增可能也增加疾病风险，但需未来研究评估。
研究设计与样本
- 对788例iPN患者（369例纯小纤维神经病、266例感觉运动型、144例纯感觉型、9例纯运动型）行全基因组测序并以PCR确认。
- 开发整合ExpansionHunter Denovo与ExpansionHunter及无监督聚类的分析流程检测RFC1扩增，与重复引物PCR验证一致性97.2%。
主要发现
- 双等位RFC1扩增在iPN中占2.3%（18/788），对照仅1/778（Fisher精确P=7×10⁻⁵）。
- 双等位扩增频率：纯感觉神经病6.9%（10/144）、小纤维神经病1.1%（4/369）、感觉运动神经病1.5%（4/266）。
- 单等位扩增在iPN中为9.1%、对照为7.2%，差异无统计学显著性（Fisher精确P=0.17）。
- 单等位携带者中未发现另一等位的第二突变或扩增。
关键数值与推荐
- 双等位RFC1扩增在iPN中占2.3%（18/788），对照1/778，Fisher精确P=7×10⁻⁵。
- 纯感觉神经病双等位扩增频率6.9%（10/144）。
- 小纤维神经病双等位扩增频率1.1%（4/369），感觉运动神经病1.5%（4/266）。
- 单等位扩增频率iPN 9.1%、对照7.2%，Fisher精确P=0.17。
临床怎么用
- 对特发性周围神经病患者应考虑RFC1重复扩增筛查。
- 运动神经受累不应作为排除RFC1筛查的依据。
- 纯感觉神经病患者筛查阳性率较高，尤应关注。
局限性
- 单等位扩增与疾病风险的关联未达统计学显著性，需未来研究验证。
- 单等位携带者中未发现第二突变或扩增，其致病机制尚不明确。
以上解读依据论文摘要（全文未开放获取或许可不允许翻译转载）。
原文
OBJECTIVE: Biallelic intronic AAGGG repeat expansions in RFC1 cause cerebellar ataxia with neuropathy and vestibular areflexia syndrome and may also contribute to isolated sensory neuropathy. The clinical significance of both heterozygous and homozygous (biallelic) RFC1 expansions in more diverse patient populations remains unclear-partly due to the absence of accurate, user-friendly computational pipelines specifically tailored for tandem repeat analysis. METHODS: To discern the relationship between RFC1 expansions and idiopathic peripheral neuropathy (iPN), we performed whole-genome sequencing (WGS) followed by polymerase chain reaction (PCR)-based confirmation in a large, well-characterized US cohort consisting of 788 patients with iPN (369 pure small fiber neuropathy (SFN), 266 sensorimotor, 144 pure sensory, and 9 pure motor). We developed an integrative pipeline combining ExpansionHunter Denovo and Expansion Hunter coupled with unsupervised clustering to reliably detect and genotype RFC1 expansions from short-read WGS data, achieving 97.2% concordance with repeat-primed PCR-based validation. RESULTS: Biallelic RFC1 expansions were present in only 1 out of 778 controls but present in 18 out of 788 (2.3%) patients with iPN (Fisher's exact p = 7 × 10-5), including 6.9% (10/144) of pure sensory, 1.1% (4/369) of SFN, and 1.5% (4/266) of sensorimotor neuropathy. These data indicate that motor nerve involvement should not exclude patients from RFC1 repeat screening. Monoallelic expansions were observed at a nominally higher frequency in iPN than in controls (9.1% vs 7.2%), but this difference did not reach statistical significance (Fisher's exact p = 0.17). We also found no evidence of second mutations or expansions on the other allele among monoallelic carriers. INTERPRETATION: Our approach provides a robust, cost-effective method for detecting RFC1 expansions from WGS data. Our findings indicate that homozygous (biallelic) AAGGG repeat expansions in RFC1 contribute to development of iPN. Heterozygous expansions may also confer disease risk, but future studies are needed to assess this observation and explore any phenotypic differences with biallelic cases. ANN NEUROL 2026;100:95-108.
引用
- Tang Z, Ovunc SS, Iwase R, et al. Homozygous RFC1 AAGGG Repeat Expansions Are Common in Idiopathic Peripheral Neuropathy. Ann Neurol. 2026. PMID: 41964406. doi:10.1002/ana.78226
供执业医师工作参考，不替代临床判断；数值与分级以指南原文为准。