Clinical and genetic analysis and identifiction of casative genes for adult leukoencephalopathy

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15459
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52020:Neurology-related
• Research Institution: Yokohama City University
• Principal Investigator: Miyake Ryoko 横浜市立大学, 医学研究科, 客員研究員 (10760184)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: leukoencephalopathy / exome / NOTCH2NLC

Outline of Final Research Achievements

Leukoencephalopathies comprise a broad spectrum of disorders, but the genetic background of adult leukoencephalopathies has rarely been assessed. We analyzed 110 Japanese patients with adult leukoencephalopathy using custom-designed gene panel (CDGP), whole-exome sequencing (WES) and repeat-primed PCR (RP-PCR) for detecting GGC expansion in NOTCH2NLC, which was identified as the cause of neuronal intranuclear inclusion disease (NIID). As for CDGP and WES, the patients with “likely pathogenic” and “pathogenic” variants were picked up according to American College of Medical Genetics guidelines.
As the results of CDGP and WES, we found 11 patients with “likely pathogenic” / “pathogenic” NOTCH3 variants as the major cause of adult leukoencephalopathy detectable by short-read sequencing. As the result of RP-PCR, we found 12 patients with GGC expansion in NOTCH2NLC. Our results indicate that NIID and CADASIL are two major causes of Japanese adult non-acquired leukoencephalopathy.

Free Research Field

神経遺伝学

Academic Significance and Societal Importance of the Research Achievements

成人白質脳症において多検体を用いて遺伝学的背景の解明を試みた研究は少なく、イギリス、ブラジルの施設で行われた研究（Lynch DSらBrain 140, 1204-1211, 2017）以外ほとんど見当たらない。我々は日本人成人白質脳症患者において110例（先行研究と合わせてた症例数）のうち28例（25.5%）において原因遺伝子を明らかにし、12例がNIID、11例がCADASILでNIIDとCADASILであることを示した。上記2疾患が日本人成人白質脳症の2大原因であることを明らかにした（Okubo Mら、業績参照）ことは、実臨床に非常に有益な情報を与えるものであると考えられる。