Yamada, Mamiko



School of Medicine, Center for Medical Genetics (Shinanomachi)


Senior Assistant Professor (Non-tenured)/Assistant Professor (Non-tenured)

Career 【 Display / hide

  • 2011.04

    慶應義塾大学病院, 初期臨床研修医

  • 2014.04

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

  • 2017.04

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

  • 2018.04

    Keio University, Health Center, 助教

  • 2018.04

    慶應義塾大学医学部臨床遺伝学センター, 助教

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Academic Background 【 Display / hide

  • 2005.04

    Keio University, 医学部

    University, Graduated

Academic Degrees 【 Display / hide

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


Papers 【 Display / hide

  • PDIVAS: Pathogenicity predictor for Deep-Intronic Variants causing Aberrant Splicing

    Kurosawa R., Iida K., Ajiro M., Awaya T., Yamada M., Kosaki K., Hagiwara M.

    BMC Genomics (BMC Genomics)  24 ( 1 )  2023.12

     View Summary

    Background: Deep-intronic variants that alter RNA splicing were ineffectively evaluated in the search for the cause of genetic diseases. Determination of such pathogenic variants from a vast number of deep-intronic variants (approximately 1,500,000 variants per individual) represents a technical challenge to researchers. Thus, we developed a Pathogenicity predictor for Deep-Intronic Variants causing Aberrant Splicing (PDIVAS) to easily detect pathogenic deep-intronic variants. Results: PDIVAS was trained on an ensemble machine-learning algorithm to classify pathogenic and benign variants in a curated dataset. The dataset consists of manually curated pathogenic splice-altering variants (SAVs) and commonly observed benign variants within deep introns. Splicing features and a splicing constraint metric were used to maximize the predictive sensitivity and specificity, respectively. PDIVAS showed an average precision of 0.92 and a maximum MCC of 0.88 in classifying these variants, which were the best of the previous predictors. When PDIVAS was applied to genome sequencing analysis on a threshold with 95% sensitivity for reported pathogenic SAVs, an average of 27 pathogenic candidates were extracted per individual. Furthermore, the causative variants in simulated patient genomes were more efficiently prioritized than the previous predictors. Conclusion: Incorporating PDIVAS into variant interpretation pipelines will enable efficient detection of disease-causing deep-intronic SAVs and contribute to improving the diagnostic yield. PDIVAS is publicly available at https://github.com/shiro-kur/PDIVAS . Graphical abstract: [Figure not available: see fulltext.].

  • Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report

    Ouchi S., Ishii K., Kosaki K., Suzuki H., Yamada M., Takenouchi T., Tamaoka A.

    BMC Neurology (BMC Neurology)  23 ( 1 )  2023.12

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    Background: Individuals with variants of cytochrome c oxidase assembly factor 7 (COA7), a mitochondrial functional-related gene, exhibit symptoms of spinocerebellar ataxia with axonal neuropathy before the age of 20. However, COA7 variants with parkinsonism or adult-onset type cases have not been described. Case presentation: We report the case of a patient who developed cerebellar symptoms and slowly progressive sensory and motor neuropathy in the extremities, similar to Charcot-Marie-Tooth disease, at age 30, followed by parkinsonism at age 58. Exome analysis revealed COA7 missense mutation in homozygotes (NM_023077.2:c.17A > G, NP_075565.2: p.Asp6Gly). Dopamine transporter single-photon emission computed tomography using a 123I-Ioflupane revealed clear hypo-accumulation in the bilateral striatum. However, 123I-metaiodobenzylguanidine myocardial scintigraphy showed normal sympathetic nerve function. Levodopa administration improved parkinsonism in this patient. Conclusions: COA7 gene variants may have caused parkinsonism in this case because mitochondrial function-related genes, such as parkin and PINK1, are known causative genes in some familial Parkinson’s diseases.

  • Oculofaciocardiodental syndrome caused by a novel BCOR variant

    Yamashita T., Hotta J., Jogu Y., Sakai E., Ono C., Bamba H., Suzuki H., Yamada M., Takenouchi T., Kosaki K., Yorifuji T., Hamazaki T., Seto T.

    Human Genome Variation (Human Genome Variation)  10 ( 1 )  2023.12

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    Oculofaciocardiodental syndrome is caused by variants in the BCL6 corepressor (BCOR) gene. We identified a novel heterozygous frameshift variant, NM_001123385.2(BCOR):c.2326del, that arose de novo in a Japanese girl with characteristic facial features, congenital heart disease, bilateral syndactyly of toes 2 and 3, congenital cataracts, dental abnormalities, and mild intellectual disability. Reports of BCOR variants are rare, and further case accumulation is warranted.

  • BMP2 is a potential causative gene for isolated dextrocardia situs solitus

    Yogi A., Iemura R., Nakatani H., Takasawa K., Gau M., Yamauchi T., Yoshida M., Moriyama K., Ishii T., Hosokawa S., Yamada M., Suzuki H., Kosaki K., Kashimada K., Morio T.

    European Journal of Medical Genetics (European Journal of Medical Genetics)  66 ( 9 )  2023.09

    ISSN  17697212

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    BMP2 (bone morphogenic protein-2) is a member of the TGF-β superfamily and has essential roles in the development of multiple organs, including osteogenesis. Because of its crucial role in organ and skeletal development, Bmp2 null mice is fetal lethal. The recent report has characterized multiple patients with BMP2 haploinsufficiency, describing individuals with BMP2 sequence variants and deletions associated with short stature without endocrinological abnormalities, a recognizable craniofacial gestalt, skeletal anomalies, and congenital heart disease. However, due to a small number of reported patients with BMP2 haploinsufficiency, the genotype and phenotype correlations are not fully understood. We experienced a family of BMP2 haploinsufficiency with a novel frameshift variant NM_001200.4: c.231dup (p.Tyr78Leufs*38) which was predicted to be “pathogenic” by the American College of Genetics and Genomics (ACGM) criteria. In addition to short stature, impaired hearing ability and minor skeletal deformities, the proband exhibited isolated dextrocardia situs solitus without cardiac anomalies and abnormal locations of other visceral organs. Our study would shed light on the crucial role of BMP2 in determining the cardiac axis, and further studies are needed to assemble more cases to elucidate BMP2 role in human heart development.

  • Heterozygous loss-of-function DHX9 variants are associated with neurodevelopmental disorders: Human genetic and experimental evidences

    Yamada M., Nitta Y., Uehara T., Suzuki H., Miya F., Takenouchi T., Tamura M., Ayabe S., Yoshiki A., Maeno A., Saga Y., Furuse T., Yamada I., Okamoto N., Kosaki K., Sugie A.

    European Journal of Medical Genetics (European Journal of Medical Genetics)  66 ( 8 )  2023.08

    ISSN  17697212

     View Summary

    DExH-box helicases are involved in unwinding of RNA and DNA. Among the 16 DExH-box genes, monoallelic variants of DHX16, DHX30, DHX34, and DHX37 are known to be associated with neurodevelopmental disorders. In particular, DHX30 is well established as a causative gene for neurodevelopmental disorders. Germline variants of DHX9, the closest homolog of DHX30, have not been reported until now as being associated with congenital disorders in humans, except that one de novo heterozygous variant, p.(Arg1052Gln) of the gene was identified during comprehensive screening in a patient with autism; unfortunately, the phenotypic details of this individual are unknown. Herein, we report a patients with a heterozygous de novo missense variant, p.(Gly414Arg) of DHX9 who presented with a short stature, intellectual disability, and ventricular non-compaction cardiomyopathy. The variant was located in the glycine codon of the ATP-binding site, G-C-G-K-T. To assess the pathogenicity of these variants, we generated transgenic Drosophila lines expressing human wild-type and mutant DHX9 proteins: 1) the mutant proteins showed aberrant localization both in the nucleus and the cytoplasm; 2) ectopic expression of wild-type protein in the visual system led to the rough eye phenotype, whereas expression of the mutant proteins had minimal effect; 3) overexpression of the wild-type protein in the retina led to a reduction in axonal numbers, whereas expression of the mutant proteins had a less pronounced effect. Furthermore, in a gene-editing experiment of Dhx9 G416 to R416, corresponding to p.(Gly414Arg) in humans, heterozygous mice showed a reduced body size, reduced emotionality, and cardiac conduction abnormality. In conclusion, we established that heterozygosity for a loss-of-function variant of DHX9 can lead to a new neurodevelopmental disorder.

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Papers, etc., Registered in KOARA 【 Display / hide

Reviews, Commentaries, etc. 【 Display / hide

Presentations 【 Display / hide

  • デノボ均衡型相互転座t(4:18)(q31;q11.2)の「不均衡」を長鎖シーケンサーで読み解く




    Oral presentation (general)

  • Role of whole genome sequencing in detecting compound heterozygotes for single nucleotide variant and structural variant.

    Mamiko Yamada, Taiki Shima, Hiroyuki Adachi, Akiko Noguchi, Hisato Suzuki, Tsutomu Takahashi, Kenjiro Kosaki


    Oral presentation (general)

  • トランスクリプトームおよび全ゲノム解析を用いたキメラ遺伝子形成による先天性遺伝性疾患発症機序の解明




    Oral presentation (general)

  • フマラーゼ異常症の診断を契機に、家系員に同一FH遺伝子のバリアントによる遺伝性平滑筋腫症および腎細胞癌症候群の二次的所見を得た事例




    Poster presentation

  • Chimeric transcript formation as a new pathogenetic mechanism of rare and undiagnosed diseases.

    Mamiko Yamada, Hisato Suzuki, Seiji Mizuno, Akiko Watanabe, Tomoko Uehara, Toshiki Takenouchi, Kenjiro Kosaki



    Oral presentation (general)

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

  • 長鎖型次世代シーケンシング技術を用いた口唇口蓋裂の発症機序の解明


    基盤研究(C), Principal investigator

  • 遺伝性疾患の診断限界を超えるための長鎖型シーケンサーによる標的領域の解析技術


    慶應医師会, Research grant, No Setting

  • 長鎖型シーケンサー全ゲノム解析の革新:未診断疾患小児の病因解明


    資生堂, 資生堂女性研究者グラント, Research grant, Principal investigator

  • 小児遺伝性疾患のゲノム・エピゲノム異常を含めた全変異種の同時検出法の開発:ネルソン・プロジェクト


    公益財団法人小児医学研究振興財団, Research grant, Principal investigator

  • Adaptive samplingによる長鎖型シーケンサーの臨床応用の実現


    慶應義塾大学, 福澤基金, Research grant, Principal investigator

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Awards 【 Display / hide

  • 第62回日本先天異常学会優秀演題賞


    Type of Award: Award from Japanese society, conference, symposium, etc.

  • 日本先天異常学会2021年度奨励賞


    Type of Award: Other

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


    Type of Award: Award from international society, conference, symposium, etc.

  • 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: International academic award (Japan or overseas)

  • 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: Award from Japanese society, conference, symposium, etc.


Memberships in Academic Societies 【 Display / hide

  • 日本小児内分泌学会, 

  • 日本小児科学会, 

  • The Japan Society of Human Genetics

  • The Japanese teratology society

  • The Japanese association of school health


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