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<p>Neuronal intranuclear inclusion disease (NIID) is typically diagnosed through molecular techniques or skin biopsy, with GGC repeat expansions in <i>NOTCH2NLC</i> being a key molecular marker. This study investigated an NIID patient who had received skin biopsy confirmation but showed no detectable GGC repeat expansions in <i>NOTCH2NLC</i> through standard genetic testing. Using whole genome long-read sequencing (LRS), we identified GGC expansions in <i>NOTCH2NLC</i> along with three previously undetected upstream variants that had caused the initial false-negative molecular diagnosis. We further analyzed 501 essential tremor patients and 361 whole genome LRS datasets to characterize the region surrounding the GGC repeat expansion, revealing that these variants are rare. Our findings demonstrate that rare <i>NOTCH2NLC</i> variants can lead to false-negative molecular diagnoses in NIID patients, emphasizing the value of comprehensive genotyping through LRS. These results provide important guidance for developing diagnostic strategies for similar cases in the future.</p>

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Detection and characterization of rare variants in NOTCH2NLC causing false negative molecular diagnosis through long-read sequencing

  • 期刊论文

  • 发表日期：

    2025年6月13日

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  • Xiaosheng Zheng,
  • Nan Jin,
  • Peng Liu,
  • Dehao Yang,
  • Lebo Wang,
  • Yixin Kang,
  • Jiaxiang Li,
  • Zhidong Cen,
  • Wei Luo

摘要

Neuronal intranuclear inclusion disease (NIID) is typically diagnosed through molecular techniques or skin biopsy, with GGC repeat expansions in NOTCH2NLC being a key molecular marker. This study investigated an NIID patient who had received skin biopsy confirmation but showed no detectable GGC repeat expansions in NOTCH2NLC through standard genetic testing. Using whole genome long-read sequencing (LRS), we identified GGC expansions in NOTCH2NLC along with three previously undetected upstream variants that had caused the initial false-negative molecular diagnosis. We further analyzed 501 essential tremor patients and 361 whole genome LRS datasets to characterize the region surrounding the GGC repeat expansion, revealing that these variants are rare. Our findings demonstrate that rare NOTCH2NLC variants can lead to false-negative molecular diagnoses in NIID patients, emphasizing the value of comprehensive genotyping through LRS. These results provide important guidance for developing diagnostic strategies for similar cases in the future.