人工知能(AI)とRNA-Seqの融合による遺伝性小児神経疾患の新たな病因解明

通过人工智能 (AI) 和 RNA-Seq 的融合阐明遗传性​​儿科神经系统疾病的新病因

• 批准号: 20K08236
• 负责人: 加藤 光広
• 金额: $ 2.75万
• 依托单位: Showa University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2020
• 资助国家: 日本
• 起止时间: 2020-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-20K08236/
• 关键词: 人工知能; スプライス異常; RT-PCR; エクソーム; RNA-Seq; エクソーム解析; 深層学習

小児期発症の希少難治性神経疾患は遺伝性が高い。私たちは1000家系以上でエクソーム解析を行い、多数の原因遺伝子を明らかにしてきたが、全ゲノム解析でも原因同定率は60%程度であり、新たな解析方法の開発が求められている。エクソーム解析では原因が不明であった脳形成異常例に、人工知能(AI)技術を用いたスプライス部位の予測アルゴリズムSpliceAIを用いて解析したところ、劣性遺伝の小頭症3家系6名に共通するスプライス変異を同定した。同定した変異部位はエクソンから40塩基対以上離れたイントロンに存在し、従来のスプライス部位予測アルゴリズムでは検出できていなかった。その後、株化リンパ球を用いた発現実験を行い、RT-PCRで正常とは異なる長さの転写産物を認め、スプライス異常を確認した。スプライス異常検出におけるAI技術の有用性を確認した。SpliceAIのアルゴリズムをエクソームデータの解析プラットフォームに組み込み、新規にエクソーム解析を行った発端者295例＋家族193検体の計488検体についてスプライス異常の検出を試みた。その結果、発端者50例でスプライス異常が予測された。多くは親由来で病原性は否定的であったが、7例で疾患原因と考えられるde novoのスプライス異常が予測される変異を認めた。うち2例はSpliceAIのスコアは低かったが、ACMGガイドラインではpathogenicと判定された。1例で株化リンパ球を用いた発現実験を計画し、RNA-Seq解析では株化リンパ球での発現がなかったため、強制発現実験のための細胞培養を進めている。他に10家系12例でスプライス異常を同定した。うち1例はエクソンイントロン境界から27bp離れていたが、SpliceAIのスコアは高く、RT-PCRを行い21アミノ酸のインフレーム挿入が生じるスプライス異常であることを確認した。

In the childhood stage, the symptoms are rare, the symptoms are rare, the treatment of sexual diseases is abnormal, and the sexual symptoms are high. There are more than 1000 family members in the private sector, most of the causes are the same, and the new method of analysis is used to analyze the causes. An analysis of the causes of unknown diseases causes the formation of a common practice, artificial knowledge (AI) technology uses the parts of artificial knowledge (AI) technology to analyze the causes of unknown diseases, the use of artificial knowledge technology (artificial knowledge technology), the use of artificial knowledge technology, the In the same way, you can tell me that there is something wrong with the location, which is more than 40 per cent. there is a connection between the location and the location. After the treatment, the chemical plant is used to make sure that it is possible to make sure that it is not possible to make sure that it is used to make sure that it is not necessary to make sure that it is in the normal state of the RT-PCR. It is common to confirm the usefulness of AI technology. There are two hundred and fifty-five people in the SpliceAI family. There are two hundred and eighty-eight people in the family. The results showed that 50 patients were often diagnosed with severe hepatitis. The etiology of multiple diseases was negative, the causes of diseases were negative, and the causes of diseases were examined in 7 cases. The etiology of de novo was often confirmed. There were 2 cases of SpliceAI syndrome, and the other 2 cases were diagnosed with low temperature, ACMG syndrome and pathogenic syndrome. In 1 case, the cell culture system was used to improve the quality of the cell culture, and the results were analyzed by RNA-Seq and RNA-Seq analysis. He has 10 pedigrees and 12 patients. They often agree with each other. In one case, there was an increase in the level of 27bp, SpliceAII, and RT-PCR, and there was an increase in the number of patients in the health care department.

项目成果

A boy with biallelic frameshift variants in TTC5 and brain malformation resembling tubulinopathies

• DOI: 10.1038/s10038-021-00953-7
• 发表时间: 2021-06-25
• 期刊: JOURNAL OF HUMAN GENETICS
• 影响因子: 3.5
• 作者: Miyamoto，Sachiko;Kato，Mitsuhiro;Saitsu，Hirotomo
• 通讯作者: Saitsu，Hirotomo

A novel de novo KCNB1 variant altering channel characteristics in a patient with periventricular heterotopia, abnormal corpus callosum, and mild seizure outcome

• DOI: 10.1038/s10038-022-01090-5
• 发表时间: 2022-10
• 期刊: Journal of Human Genetics
• 影响因子: 3.5
• 作者: Takuya Hiraide;T. Akita;Kenji Uematsu;Sachiko Miyamoto;M. Nakashima;Masayuki Sasaki;A. Fukuda;Mitsuhiro Kato;H. Saitsu

Comprehensive genetic analysis confers high diagnostic yield in 16 Japanese patients with corpus callosum anomalies

• DOI: 10.1038/s10038-021-00932-y
• 发表时间: 2021-05
• 期刊: Journal of Human Genetics
• 影响因子: 3.5
• 作者: Sachiko Miyamoto;Mitsuhiro Kato;Takuya Hiraide;T. Shiohama;T. Goto;Akira Hojo;Akio Ebata;Manabu Suzuki;Kozue Kobayashi;P. Chong;R. Kira;H. Matsushita;H. Ikeda;K. Hoshino;M. Matsufuji;N. Moriyama;Masayuki Furuyama;Tatsuya Yamamoto;M. Nakashima;H. Saitsu

Genetics of neonatal-onset epileptic encephalopathies:A tribute to Prof. Ohtahara

新生儿癫痫性脑病的遗传学：向 Ohtahara 教授致敬

• 发表时间: 2020
• 作者: Muraoka M;Maekawa S;Katoh R;Komiyama Y;Nakakuki N;Takada H;Matsuda S;Suzuki Y;Sato M;Tatsumi A;Miura M;Amemiya F;Shindo H;Takano S;Fukasawa M;Yamauchi K;Yamaguchi T;Nakayama Y;Inoue T;Enomoto N.;Mitsuhiro Kato
• 通讯作者: Mitsuhiro Kato

Discordant phenotypes in monozygotic twins with STXBP1 mutation: A case report

STXBP1 突变同卵双胞胎的不一致表型：病例报告

• DOI: 10.1016/j.seizure.2022.06.019
• 发表时间: 2022
• 期刊: Seizure
• 作者: Kobayashi Hikaru、Matsushige Takeshi、Hoshide Madoka、Hoshide M;Hidaka I;Ichiyama T;Kato M. et al.
• 通讯作者: Kato M. et al.