Yamada, Mamiko

写真a

Affiliation

School of Medicine, Center for Medical Genetics (Shinanomachi)

Position

Instructor

Career 【 Display / hide

  • 2011.04
    -
    2013.03

    慶應義塾大学病院, 初期臨床研修医

  • 2014.04
    -
    2017.03

    Keio University, Department of Pediatrics, 助教(専修医)

  • 2017.04
    -
    2018.03

    Keio University, Department of Pediatrics, 助教(小児科)

  • 2018.04
    -
    2019.03

    Keio University, Health Center, 助教

  • 2018.04
    -
    Present

    慶應義塾大学医学部臨床遺伝学センター

Academic Background 【 Display / hide

  • 2005.04
    -
    2011.03

    Keio University, 医学部

    University, Graduated

Academic Degrees 【 Display / hide

  • 博士(医学), Keio University, Dissertation, 2020.03

 

Papers 【 Display / hide

  • Learning disability and myoclonic epilepsy associated with apparently synonymous but splice-disrupting JMJD1C variant that led to 21 bp deletion of the transcript

     2020.09

    Research paper (scientific journal), Joint Work, Accepted

  • Heterozygous nonsense variant of CHD8 in a patient with forme-fruste Marfan syndrome and intellectual disability

     2020.09

    Research paper (scientific journal), Joint Work, Accepted

  • 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)   2020.08

    Research paper (scientific journal), Joint Work, Accepted,  ISSN  15524825

     View Summary

    © 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)   2020.08

    Joint Work, Accepted,  ISSN  15524825

     View Summary

    © 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)   2020.06

    Joint Work

     View Summary

    © 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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Reviews, Commentaries, etc. 【 Display / hide

Presentations 【 Display / hide

  • 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, 2020.01, Oral Presentation(general)

  • 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, 2019.11, Oral Presentation(general)

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

    Mamiko Yamada

    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, 2019.07, Oral Presentation(general)

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

    European Human Genetics Conference, 2019.06, Oral Presentation(general)

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

    Yamada Mamiko

    第41回日本小児遺伝学会学術集会, 2019.01, Oral Presentation(general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

  • 小児先天性遺伝性疾患における新たな発症機序の解明―ゲノム構造異常によるキメラ遺伝子形成の網羅的解析―

    2020.09
    -
    2021.03

    Research grant, Principal Investigator

  • 哺乳不良を伴う新生児および乳児を対象とした、原因疾患の早期診断のための遺伝学的アプローチ:人工知能によるスプライシング異常の検出およびエクソーム・RNA統合解析の有用性の検討

    2020.04
    -
    2021.09

    Research grant, Principal Investigator

  • 遺伝性疾患の発症機序としてのキメラ遺伝子形成:全ゲノム・RNA 統合解析による検討

    2020.04
    -
    2021.03

    Research grant, Principal Investigator

  • 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

    2019.04
    -
    2021.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 山田 茉未子, Grant-in-Aid for Early-Career Scientists , Principal Investigator

  • 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

    2019.04
    -
    2020.03

    山田茉未子, ゲノム科学・バイオインフォマティクス, Research grant, Principal Investigator

Awards 【 Display / hide

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

    2020.01

    Type of Award: Awards of International Conference, Council and Symposium

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

    2019.07,  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

    Type of Award: Awards of International Conference, Council and Symposium

  • 優秀演題賞、日本小児遺伝学会

    2019.01, 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

    Type of Award: Awards of National Conference, Council and Symposium

 

Memberships in Academic Societies 【 Display / hide

  • 日本小児内分泌学会, 

    2015
    -
    Present
  • 日本小児科学会, 

    2013.04
    -
    Present
  • The Japan Society of Human Genetics

     
  • The Japanese teratology society

     
  • The Japanese association of school health

     

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