Revealing pathogenesis of noncoding repeat expansion diseases using long-read sequencing

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03588
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Okayama University (2022); The University of Tokyo (2020-2021)
• Principal Investigator: Ishiura Hiroyuki 岡山大学, 医歯薬学域, 教授 (40632849)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: ロングリードシーケンス / リピート伸長病

Outline of Final Research Achievements

We established a pipeline to extract repeat expansion mutations from short read whole genome sequencing and applied it to patients with myoclonus epilepsy, leukoencephalopathy, muscle diseases, and ataxia. Clinical genetic analysis of oculopharyngodistal myopathy and neuronal nuclear inclusion body disease was performed, and novel clinical presentations were reported as papers. Long-read sequencing was also analyzed to decipher full-length repeat sequences in patients with already known repeat expansion mutations. Cloning methods for repeat extension sequences were also discussed. We proposed the concept of FNOP-spectrum disorder, which describes clinical manifestations ranging from leukoencephalopathy to ophthalmopharyngeal myopathy based on CGG repeat expansion mutations.

Free Research Field

神経遺伝学

Academic Significance and Societal Importance of the Research Achievements

申請者は神経筋疾患においてリピート伸長病を多く同定してきた。リピート伸長変異は、通常の解析では見つからないことが多いため、専用の解析方法の適応が必要になる。本研究では、リピート伸長変異に注目し新規リピート伸長変異の同定を目指すとともに、既に同定したリピート伸長病の病態に迫ることを目的としている。これまで、リピート病の研究を進めるとともに、眼咽頭遠位型ミオパチー1型の臨床病型の広がり、神経核内封入体病の臨床像の広がりについて報告するとともに、新しい疾患概念FNOP-spectrum disorderを提唱した。