山田 茉未子 (ヤマダ マミコ)

Yamada, Mamiko

写真a

所属(所属キャンパス)

医学部 臨床遺伝学センター (信濃町)

職名

助教(有期)

経歴 【 表示 / 非表示

  • 2011年04月
    -
    2013年03月

    慶應義塾大学病院, 初期臨床研修医

  • 2014年04月
    -
    2017年03月

    慶應義塾大学小児科学教室, 助教(専修医)

  • 2017年04月
    -
    2018年03月

    慶應義塾大学小児科学教室, 助教(小児科)

  • 2018年04月
    -
    2019年03月

    慶應義塾大学保健管理センター, 助教

  • 2018年04月
    -
    継続中

    慶應義塾大学医学部臨床遺伝学センター

学歴 【 表示 / 非表示

  • 2005年04月
    -
    2011年03月

    慶應義塾, 医学部

    大学, 卒業

学位 【 表示 / 非表示

  • 博士(医学), 慶應義塾, 論文, 2020年03月

 

論文 【 表示 / 非表示

  • Biallelic Mutations in the LSR Gene Cause a Novel Type of Infantile Intrahepatic Cholestasis

    Uehara T., Yamada M., Umetsu S., Nittono H., Suzuki H., Fujisawa T., Takenouchi T., Inui A., Kosaki K.

    Journal of Pediatrics (Journal of Pediatrics)  221   251 - 254 2020年04月

    研究論文(学術雑誌), 査読有り,  ISSN  00223476

     概要を見る

    © 2020 Elsevier Inc. We identified biallelic pathogenic mutations in the Lipolysis-stimulated lipoprotein receptor (LSR) gene in a patient with infantile intrahepatic cholestasis. We established that mutations in the LSR gene, which encodes a protein which is critical for the formation of tricellular tight junctions in the liver, are a novel cause of pediatric cholestasis.

  • Shortfall of exome analysis for diagnosis of Shwachman-Diamond syndrome: Mismapping due to the pseudogene SBDSP1

    Yamada M., Uehara T., Suzuki H., Takenouchi T., Inui A., Ikemiyagi M., Kamimaki I., Kosaki K.

    American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A)  182 ( 7 ) 1631 - 1636 2020年

    ISSN  15524825

     概要を見る

    © 2020 Wiley Periodicals, Inc. Shwachman-Diamond syndrome characterized by metaphyseal dysplasia, pancreatic insufficiency, and pancytopenia is caused by biallelic mutations in SBDS. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. Here, we report two unrelated patients with Shwachman-Diamond syndrome who were shown to be compound heterozygotes for relatively frequent pathogenic alleles (the 258+2T>C allele and another allele composed of 183-184TA>CT and 201A>G) using an established polymerase chain reaction sequencing assay with SBDS-specific primers. Exome analysis of the patients showed discrepant results: 258+2T>C with variant allele frequency around 0.85, and no variants detected for the 183-184TA>CT allele. Parental exome analysis of the two families further supported this notion. Confronted with two patients with an unexpected segregation pattern, we performed a transcriptome analysis of peripheral blood-derived mRNA to demonstrate that the results were compatible with those obtained using SBDS-specific PCR primers. Both alleles could be accounted for by gene conversion events. The diagnostic discrepancy can be accounted for by a decreased efficiency in the computational mapping of the reads with 183-184TA>CT and 201A>G to the reference sequence of the SBDS locus during exome analysis. This report highlights the pitfall of exome analysis for genes with pseudogenes, such as SBDS and the alternative use of RNA-seq is recommended to circumvent this problem.

  • Protein elongation variant of PUF60: Milder phenotypic end of the Verheij syndrome

    Yamada M., Uehara T., Suzuki H., Takenouchi T., Kosaki K.

    American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A)  2020年

    ISSN  15524825

     概要を見る

    © 2020 Wiley Periodicals LLC The PUF60 gene encodes a ubiquitously expressed essential splicing factor that is recruited to the U2snRNA complex. The complex binds to the 3′ splice site of exons in specific target genes and regulates the inclusion or exclusion of such exons. Recently, pathogenic variants of PUF60 have been shown to cause a relatively specific and potentially recognizable pattern of malformation referred to as Verheij syndrome. Here, we report a 12-year-old female patient with a de novo mutation in PUF60 whose phenotype was representative of the milder end of the phenotypic spectrum of Verheij syndrome; the de novo mutation was a frameshift mutation p.(Ser558Cysfs*21) that resulted in the addition of 21 extra amino acids at the carboxy end of the protein. Among the frequent features of Verheij syndrome, the patient exhibited coloboma, cervical spinal segmentation defects, and borderline intellectual functioning, but lacked cardiac abnormalities, deafness, and urogenital abnormalities. The results of RNA analysis using peripheral blood showed the escape of the mutant allele from nonsense-mediated mRNA decay, possibly accounting for the mild phenotype in the presently reported patient. Based on our clinical observations, we inferred that two embryologic processes, closure of the ocular plate and cervical spinal segmentation, are particularly susceptible to deficient PUF60-mediated splicing regulation, compared with other embryogenetic processes leading to the central nervous system, heart, ear, and kidney.

  • Parallel detection of single nucleotide variants and copy number variants with exome analysis: Validation in a cohort of 700 undiagnosed patients

    Suzuki H., Yamada M., Uehara T., Takenouchi T., Kosaki K.

    American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A)  2020年

    ISSN  15524825

     概要を見る

    © 2020 The Authors. American Journal of Medical Genetics Part A published by Wiley Periodicals LLC. Copy number variants (CNVs) are significant causes of rare and undiagnosed diseases. Parallel detection of single nucleotide variants (SNVs) and CNVs with exome analysis, if feasible, would shorten the diagnostic closure in a timely manner. We validated such “parallel” approach through a cohort study of 791 undiagnosed patients. In addition to routine exome analysis, we applied an innovative algorithm EXCAVATOR2 which enhances sensitivity by paradoxically exploiting read depth data that covers nonexonic regions where baits were not originally intended to hybridize. About 48 patients had copy number variations, 42 deletions, and 6 duplications with a resolution of 0.51–14.7 mega base pairs. Importantly from a clinical standpoint, we identified three patients with “dual diagnosis” due to concurrent pathogenic CNV and SNV. We suggest “hitting two birds with one stone” approach to exome data is an efficient strategy in deciphering undiagnosed patients and may well be considered as a first-tier genetic test.

  • Diagnostic utility of integrated analysis of exome and transcriptome: Successful diagnosis of Au-Kline syndrome in a patient with submucous cleft palate, scaphocephaly, and intellectual disabilities

    Yamada M., Shiraishi Y., Uehara T., Suzuki H., Takenouchi T., Abe-Hatano C., Kurosawa K., Kosaki K.

    Molecular Genetics and Genomic Medicine (Molecular Genetics and Genomic Medicine)  2020年

     概要を見る

    © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC Background: A weakness of exome analysis lies in inability to characterize aberrant splicing other than those involving consensus donor-acceptor sequence. To overcome this limitation, we developed a novel analytic method SAVNet that combines transcriptome and exome analysis which enabled the successful detection of carriers of splicing variants in the disease-causing genes of autosomal recessive disorders within a normal cohort. However, the clinical utility of the SAVNet analysis in delineating splicing defects in patients without a diagnosis has yet to be documented. Method: We performed SAVNet analysis using the integrated analysis of exome and transcriptome analysis from the peripheral blood of the patient. The patient is an undiagnosed Japanese female patient with submucous cleft palate, scaphocephaly and intellectual disability with no words at 8 years of age. Dysmorphic features included a long face, a short palpebral fissure, thick lips with an open month, premaxillary hypoplasia, a depressed nasal bridge, and satyr ears. Result: A SAVNet analysis showed that a heterozygous intronic variant located at the −10 position of exon 5 of the HNRNPK gene on chromosome 9 created a new splice acceptor sequence “ag” and led to the incorporation of 9 intronic nucleotides into the coding sequence. The mutant protein would have three extra amino acid residues, Leu-Leu-Gln, inserted within the critical KH domain. The patient was diagnosed as having recently delineated Au–Kline syndrome, which is characterized by cleft palate, craniosynostosis, and intellectual disability. Conclusion: The successful molecular diagnosis of the presently reported patient illustrates the diagnostic utility of the SAVNet analysis as an innovative way of implementing an integrated exome-transcriptome analysis in clinical settings.

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研究発表 【 表示 / 非表示

  • Documentation of IFT172 as the nineteenth gene causative of oral-facial-digital syndrome underscores the importance of ciliary trafficking in its pathogenesis.

    2020 Western Medical Research Conference, 2020年01月, 口頭(一般)

  • Integration of exome data with transcriptome data increased detection of pathogenic variants by 20% among 179 samples.

    日本人類遺伝学会第64回大会・東アジア人類遺伝学会連合第19回大会, 2019年11月, 口頭(一般)

  • Effectiveness of integrated interpretation of exome and corresponding transcriptome data in detecting splicing variants: Population and clinical studies

    山田茉未子

    第59回日本先天異常学会・The 13th World Congress of International Cleft Lip and Palate Foundation CLEFT 2019 ICPF合同学術集会, 2019年07月, 口頭(一般)

  • Effectiveness of integrated interpretation of exome and corresponding transcriptome data in detecting splicing variants of recessive disorders

    European Human Genetics Conference, 2019年06月, 口頭(一般)

  • Integrated analysis of RNA-seq and exome data in 179 subjects unravels frequent protein-truncating splicing events out of “missense” or “silent” mutations

    山田 茉未子

    第41回日本小児遺伝学会学術集会, 2019年01月, 口頭(一般)

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競争的資金等の研究課題 【 表示 / 非表示

  • スプライシング変異の転写後配列への影響:ゲノム・トランスクリプトーム統合解析

    2019年04月
    -
    2021年03月

    文部科学省・日本学術振興会, 科学研究費助成事業, 山田 茉未子, 若手研究, 補助金,  代表

  • 人工知能を用いた原因不明肝臓疾患のスプライシング異常の検出

    2019年04月
    -
    2020年03月

    山田茉未子, ゲノム科学・バイオインフォマティクス, 補助金,  代表

受賞 【 表示 / 非表示

  • The Western society of pediatric research & Mead Johnson Nutrition Award

    2020年01月

    受賞区分: 国際学会・会議・シンポジウム等の賞

  • Gold Award, 13th World Congress of The Intentional Cleft Lip and Palate Foundation CLEFT2019

    2019年07月,  Congress of The Intentional Cleft Lip and Palate Foundation, Effectiveness of integrated interpretation of exome and corresponding transcriptome data in detecting splicing variants: Population and clinical studies

    受賞区分: 国際学会・会議・シンポジウム等の賞

  • 優秀演題賞、日本小児遺伝学会

    2019年01月, 第41回日本小児遺伝学会学術集会, Integrated analysis of RNA-seq and exome data in 179 subjects unravels frequent protein-truncating splicing events out of “missense” or “silent” mutations

    受賞区分: 国内学会・会議・シンポジウム等の賞

 

所属学協会 【 表示 / 非表示

  • 日本小児内分泌学会, 

    2015年
    -
    継続中
  • 日本小児科学会, 

    2013年04月
    -
    継続中
  • 日本人類遺伝学会

     
  • 日本先天異常学会

     
  • 日本学校保健学会

     

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