Yamada, Mamiko



School of Medicine, Center for Medical Genetics (Shinanomachi)



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


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

  • Precocious puberty in a case of Simpson–Golabi–Behmel syndrome with a de novo 240-kb deletion including GPC3

    Watanabe K., Noguchi A., Takahashi I., Yamada M., Suzuki H., Takenouchi T., Kosaki K., Takahashi T.

    Human Genome Variation (Human Genome Variation)  9 ( 1 )  2022.12

     View Summary

    Here, we report a Japanese patient with Simpson–Golabi–Behmel syndrome involving a de novo 240-kb deletion including a part of GPC3. The patient showed pre- and postnatal macrosomia associated with coarse face, macrocephaly, supernumerary nipples, and cryptorchidism and characteristically presented with precocious puberty, mostly evaluated as advanced pubertal age of 15 years at the chronological age of 11.5 years.

  • Deciphering complex rearrangements at the breakpoint of an apparently balanced reciprocal translocation t(4:18)(q31;q11.2)dn and at a cryptic deletion: Further evidence of TLL1 as a causative gene for atrial septal defect

    Yamada M., Suzuki H., Miya F., Takenouchi T., Kosaki K.

    American Journal of Medical Genetics, Part A (American Journal of Medical Genetics, Part A)  188 ( 8 ) 2472 - 2478 2022.08

    ISSN  15524825

     View Summary

    When a de novo balanced reciprocal translocation is identified in patients with multiple congenital abnormalities, attempts are often made to infer the relationship between the phenotype of the patient and genes in the proximity of the breakpoint. Here, we report a patient with intellectual disability, atrial septal defect, syndactyly, and cleft lip and palate who had an “apparently balanced” de novo reciprocal translocation t(4:18)(q31;q11.2) as well as a 7-Mb cryptic deletion spanning the HOXD cluster on chromosome 2q31 that was unrelated to the reciprocal translocation. Further analysis using a nanopore long-read sequencer showed complex rearrangements on both derivative chromosomes 4 and 18 and the deleted chromosome 2. First, the TLL1 locus, which is associated with atrial septal defect, was disrupted by the rearrangement involving chromosome 4. Second, the deleted interval at 2q31 included the entire HOXD cluster, the deletion of which is known to cause toe syndactyly, and the DLX1 and DLX2 loci, which are responsible for cleft lip and palate. Among the haplo-sensitive genes within the deleted interval on 2q31, only the RAPGEF4 gene is known to be associated with an autistic phenotype. Hence, most of the clinical features of the patient could be ascribed to specific genomic rearrangements. We have shown the effectiveness of long-read sequencing in defining, in detail, the likely effects of an apparently balanced translocation and cryptic deletion. The results of the present analysis suggest the possibility of phenotypic prediction through a detailed analysis of structural abnormalities, including balanced translocations and deletions.

  • Phenotypic overlap between cardioacrofacial dysplasia-2 and oral-facial-digital syndrome

    Yamada M., Suzuki H., Futagawa H., Takenouchi T., Miya F., Yoshihashi H., Kosaki K.

    European Journal of Medical Genetics (European Journal of Medical Genetics)  65 ( 6 )  2022.06

    ISSN  17697212

     View Summary

    Oral-facial digital (OFD) syndrome is characterized by abnormalities of the face (hypertelorism and low set-ears), oral cavity (multiple frenula, lingual hamartoma, or lobulated tongue) and extremities (postaxial polydactyly). At least 19 genes have been implicated in the development of OFD syndrome. Herein, we report the case a 13-year-old patient with atrioventricular septal defect, moderate intellectual disability, epilepsy, and features of OFD, including multiple oral frenula, and postaxial polydactyly of the hands and feet. The patient had a de novo heterozygous variant in PRKACB: chr1(GRCh37):g.84700915T > C, c.1124T > C (NM_182948.4), p.(Phe375Ser). To date, four patients with pathogenic monoallelic variants in PRKACB have been reported, and the condition associated with these variants is referred to as Cardioacrofacial dysplasia-2 (CAFD2, MIM619143). Previously reported features of this condition include congenital heart disease (e.g., atrioventricular septal defect) and postaxial polydactyly, and two of the patients had multiple oral frenula. We suggest that a significant phenotypic overlap exists between CAFD2 and OFD syndrome, in that these patients especially share the features of postaxial polydactyly and multiple oral frenula. The phenotypic similarity between patients with CAFD2 and classic OFD syndrome with an OFD1 variant might be explained by the recent in vitro experimental finding that a protein kinase A subunit encoded by PRKACB directly phosphorylates the OFD1 protein. From the standpoint of genetic counseling, OFD syndrome type1, the prototypic form of OFD, exhibits an X-linked dominant inheritance pattern, whereas other forms of OFD syndrome exhibit an autosomal recessive inheritance pattern. Recognition of CAFD2 as a differential diagnosis or forme fruste of OFD syndrome suggests that an autosomal dominant pattern of inheritance should also be considered during genetic counseling.

  • Genomic analysis of familial pancreatic cancers and intraductal papillary mucinous neoplasms: A cross-sectional study

    Abe K., Kitago M., Kosaki K., Yamada M., Iwasaki E., Kawasaki S., Mizukami K., Momozawa Y., Terao C., Yagi H., Abe Y., Hasegawa Y., Hori S., Tanaka M., Nakano Y., Kitagawa Y.

    Cancer Science (Cancer Science)  113 ( 5 ) 1821 - 1829 2022.05

    ISSN  13479032

     View Summary

    Environmental and genetic factors play a critical role in the pathogenesis of pancreatic cancer, which is likely to follow a multistep process that includes intraductal papillary mucinous neoplasm. The pathogenesis of familial pancreatic cancer has been reported; however, epidemiological characteristics and causative genes remain unclear. This study aimed to determine the relationship between the family history of pancreatic cancer and tumor malignancy and identify novel susceptible germline variants of pancreatic cancer. We performed an epidemiologic study at our institute on a cohort of 668 patients with intraductal papillary mucinous neoplasm and 242 with pancreatic cancer but without associated intraductal papillary mucinous neoplasm stratified by family history of pancreatic cancer. Whole-exome sequencing was conducted for 10 patients from seven families with familial pancreatic cancer and intraductal papillary mucinous neoplasm. We found that patients who had intraductal papillary mucinous neoplasm with positive family history of pancreatic cancer within first-degree relatives were more likely to develop malignancy in a shorter period than those without family history. Duplicate frameshift variants in TET2 c.3180dupG (p.Pro1061fs) and ASXL1 c.1934dupG (p.Gly646fs) in one family and POLN c.1194dupT (p.Glu399fs) in another were identified as pathogenic truncating germline variants which were previously recognised susceptibility genes. Moreover, PDIA2 c.1403C>T (p.Pro468Leu) and DPYSL4 c.926C>A (p.Pro309Gln) were shared in four and two patients, respectively. In particular, PDIA2 was identified as a novel candidate for one of the deleterious variants of familial pancreatic cancer.

  • Genome Analysis in Sick Neonates and Infants: High-yield Phenotypes and Contribution of Small Copy Number Variations

    Suzuki H., Nozaki M., Yoshihashi H., Imagawa K., Kajikawa D., Yamada M., Yamaguchi Y., Morisada N., Eguchi M., Ohashi S., Ninomiya S., Seto T., Tokutomi T., Hida M., Toyoshima K., Kondo M., Inui A., Kurosawa K., Kosaki R., Ito Y., Okamoto N., Kosaki K., Takenouchi T.

    Journal of Pediatrics (Journal of Pediatrics)  244   38 - 48.e1 2022.05

    ISSN  00223476

     View Summary

    Objective: To delineate the diagnostic efficacy of medical exome, whole exome, and whole genome sequencing according to primary symptoms, the contribution of small copy number variations, and the impact of molecular diagnosis on clinical management. Study design: This was a prospective study of 17 tertiary care centers in Japan, conducted between April 2019 and March 2021. Critically ill neonates and infants less than 6 months of age were recruited in neonatal intensive care units and in outpatient clinics. The patients underwent medical exome, whole exome, or whole genome sequencing as the first tier of testing. Patients with negative results after medical exome or whole exome sequencing subsequently underwent whole genome sequencing. The impact of molecular diagnosis on clinical management was evaluated through contacting primary care physicians. Results: Of the 85 patients, 41 (48%) had positive results. Based on the primary symptoms, patients with metabolic phenotypes had the highest diagnostic yield (67%, 4/6 patients), followed by renal (60%, 3/5 patients), and neurologic phenotypes (58%, 14/24 patients). Among them, 4 patients had pathogenic small copy number variations identified using whole genome sequencing. In the 41 patients with a molecular diagnosis, 20 (49%) had changes in clinical management. Conclusions: Genome analysis for critically ill neonates and infants had a high diagnostic yield for metabolic, renal, and neurologic phenotypes. Small copy number variations detected using whole genome sequencing contributed to the overall molecular diagnosis in 5% of all the patients. The resulting molecular diagnoses had a significant impact on clinical management.

display all >>

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)

display all >>

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

  • 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

  • スプライシング異常是正薬の開発を目指した、遺伝性疾患の発症機序の解明


    Research grant, Principal investigator

display all >>

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


display all >>