RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia
RFC1 repeat expansions: A recurrent cause of sensory and autonomic neuropathy with cough and ataxia
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DOI：
10.1111/ene.15310
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发表时间：
2022-03-23
影响因子：
5.1
通讯作者：
Baets, Jonathan
中科院分区：
文献类型：
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作者：
Beijer, Danique;Dohrn, Maike F.;Baets, Jonathan
背景与目的共济失调和咳嗽是遗传性感觉和自主神经病（HSAN）的罕见特征，HSAN是一组遗传原因不明的疾病。RFC 1中的双等位基因重复扩增与小脑共济失调、神经病和前庭反射消失综合征（CANVAS）相关。本研究旨在调查HSAN患者队列中RFC 1重复扩增的患病率。方法对12个HSAN家系的RFC 1基因进行重复引物PCR扩增，并进行全外显子序列分析。结果75%的患者携带致病性AAGGG基序的双等位基因扩增。与RFC 1-/-病例相比，RFC 1 +/+病例表现出更一致的阳性感觉和自主神经症状。在RFC 1 +/+队列中，传入性共济失调更为严重，小脑性共济失调是一种常见特征（21%）。结论我们证明RFC 1是（WES阴性）HSAN伴慢性咳嗽和共济失调的常见原因。RFC 1重复引物PCR的诊断率令人惊讶地高，因为HSAN在遗传上知之甚少。这种HSAN、共济失调和慢性咳嗽症状的组合代表了神经病-共济失调谱中的一个新的疾病分类实体。
Background and purpose Ataxia and cough are rare features in hereditary sensory and autonomic neuropathies (HSAN), a group of diseases of mostly unknown genetic cause. Biallelic repeat expansions in RFC1 are associated with cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS). This study aimed to investigate the prevalence of RFC1 repeat expansions in a cohort of HSAN patients. Methods After unremarkable whole-exome sequencing (WES) analysis, we performed repeat-primed PCR to detect intronic RFC1 expansions in 12 HSAN families, who all presented with chronic cough. Results In these patients, 75% carried biallelic expansions of the pathogenic AAGGG motif. Compared with RFC1-/- cases, RFC1+/+ cases presented more consistently with positive sensory and autonomic symptoms. Afferent ataxia was more severe in the RFC1+/+ cohort and cerebellar ataxia was a common feature (21%). Conclusions We demonstrate that RFC1 is a frequent cause of (WES-negative) HSAN with chronic cough and ataxia. The diagnostic yield of RFC1 repeat-primed PCR was surprisingly high, given that HSAN is genetically poorly understood. This combination of HSAN, ataxia, and chronic cough symptoms represents a new nosological entity within the neuropathy-ataxia spectrum.