Development and assessment of a pathogenic mutations search method for individuals who are difficult to identify the mutations in standard-exome analysis

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K07211
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Medical genome science
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Miya Fuyuki 東京医科歯科大学, 難治疾患研究所, 講師 (50415311)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Keywords: エクソーム解析 / 疾患遺伝子変異 / 遺伝性疾患 / 次世代シーケンサー / CNV解析 / ミトコンドリア / 全ゲノムシーケンス

Outline of Final Research Achievements

Whole-exome sequencing (WES) using next generation sequencing is a useful method to identify disease-causing mutations. However, often no candidate mutations are identified using commonly available methods. The reported success rate of WES for Mendelian diseases is around 30% worldwide.
We have developed an integrative analysis methodology to identify pathogenic mutations. The analysis methodology consists of the following 6 methods: 1) standard variants calling method, 2) detection of intermediate-size insertions and deletions (indels) using our own developed method, 3) copy number variants analysis for WES data, 4) analysis of mitochondrial DNA for WES data, and 5) domain enrichment analysis for candidate mutations. Through this combinatorial method, it becomes possible to identify variants and structural abnormalities that had been difficult to search and identify previously. Also, the method makes it possible to expand the limits of mutation detection of standard WES analysis.

Free Research Field

メディカルバイオインフォマティクス

Academic Significance and Societal Importance of the Research Achievements

我々の研究成果で疾患の遺伝子変異を同定する新たな手法論を構築し発表することで、その同定率を10%以上増やすことができた。解析手法を改良することによって、未同定疾患原因変異の新たな発見も可能であることを証明したことで、将来的な解析への応用は当然であるが、過去データの再検証で新規原因変異が同定されることも期待される。病気の原因変異が分かると、病気のメカニズム解明や薬剤ターゲット候補の発見、将来の発症予測、等に役立たせることができ、本成果は今後その一助になると考えられる。