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<p>Biallelic intronic pentanucleotide repeat expansions, mainly (AAGGG)exp and/or (ACAGG)exp in <i>RFC1</i>, are detected in cerebellar ataxia, neuropathy and vestibular areflexia syndrome, late-onset ataxia, and in a wide disease spectrum including Charcot-Marie-Tooth disease, multiple system atrophy, and Parkinson’s disease (PD). However, the genotype-phenotype correlation and underlying mechanism are mostly unknown. We screened <i>RFC1</i>-repeat expansions in 1445 patients with parkinsonism. Comprehensive genetic and clinical, and pathological assessments were performed. We report two early-onset patients with PD carrying complex biallelic pentanucleotide repeat expansions in <i>RFC1</i>. Long-read sequencing revealed a novel repeat configuration of (AGGGG)exp(AAGGG)<sub>14</sub> and a possible somatic variant of (AAGGG)exp(AATGG)exp(AAGGG)exp in the (AAGGG)exp alleles in two <i>RFC1</i>-related PD patients. RNA foci were detected in the (AGGGG)exp-expressed HEK293T cell line as well as (AAGGG)exp and (ACAGG)exp, supporting (AGGGG)exp as a novel pathogenic repeat motif. This work revealed complex genotypes with novel repeat configuration of (AGGGG)exp and possible somatic (AATGG)exp insertion in <i>RFC1</i>-related PD.</p>

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Long-read sequencing revealed complex biallelic pentanucleotide repeat expansions in RFC1-related Parkinson’s disease

  • 期刊论文

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  • 发表日期：

    2025年1月20日

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  • Peng Liu,
  • Fan Zhang,
  • Xinhui Chen,
  • Xiaosheng Zheng,
  • Miao Chen,
  • Zhiru Lin,
  • Shuqi Chen,
  • Lebo Wang,
  • Xinchen Wang,
  • Nan Jin,
  • Chenxin Ying,
  • Fei Xie,
  • Bo Wang,
  • Sheng Wu,
  • Zhidong Cen,
  • Wei Luo

摘要

Biallelic intronic pentanucleotide repeat expansions, mainly (AAGGG)exp and/or (ACAGG)exp in RFC1, are detected in cerebellar ataxia, neuropathy and vestibular areflexia syndrome, late-onset ataxia, and in a wide disease spectrum including Charcot-Marie-Tooth disease, multiple system atrophy, and Parkinson’s disease (PD). However, the genotype-phenotype correlation and underlying mechanism are mostly unknown. We screened RFC1-repeat expansions in 1445 patients with parkinsonism. Comprehensive genetic and clinical, and pathological assessments were performed. We report two early-onset patients with PD carrying complex biallelic pentanucleotide repeat expansions in RFC1. Long-read sequencing revealed a novel repeat configuration of (AGGGG)exp(AAGGG)14 and a possible somatic variant of (AAGGG)exp(AATGG)exp(AAGGG)exp in the (AAGGG)exp alleles in two RFC1-related PD patients. RNA foci were detected in the (AGGGG)exp-expressed HEK293T cell line as well as (AAGGG)exp and (ACAGG)exp, supporting (AGGGG)exp as a novel pathogenic repeat motif. This work revealed complex genotypes with novel repeat configuration of (AGGGG)exp and possible somatic (AATGG)exp insertion in RFC1-related PD.