Details of the Researcher

PHOTO

Jun Takayama
Section
Graduate School of Medicine
Job title
Associate Professor
Degree

  • 博士（理学）（東京大学）

  • 修士（理学）（東京大学）

e-Rad No.
20574114
Profile
学部教育時代から、生物学の実験と理論の両方を扱えるよう訓練されてきました。ゲノミクス、バイオインフォマティクス、システムバイオロジー、生物物理学と、少しずつ分野を変えながらも、常に生物学を数理的に扱いたいと考えていました。そんな折、2012年に偶然、遺伝統計学に出会い、そこから遺伝学理論の虜になっています。

元々、なぜ自分が世界に存在するかに興味を持っており、生物学の道を志しました。認識論の基礎として神経科学を、実存の基礎として生殖生物学を研究しましたが、なかなか本質を掴みきれずにおりました。遺伝学理論に取り憑かれたのは、有効集団サイズの概念や遺伝子プールの概念に触れ、自分が今まで確固たるものと信じていた個体という単位が、実は単なるランダムサンプリングの結果にすぎず、本質はアリル頻度にあるという集団遺伝学の基本的なモデル（Wright-Fisherモデル）に衝撃が走ったからに他なりません。日々、遺伝学の理論を学ぶにつけ、数理的な理論が導く深い部分での概念同士の結びつきに感動を覚えています。

Research History 6

  • 2021/01 - Present
    Tohoku University　School of Medicine　Associate Professor

  • 2020/04 - 2020/12
    Tohoku University　Advanced Research Center for Innovations in Next-Generation Medicine Research Section　Senior Assistant Professor

  • 2018/04 - 2020/03
    Tohoku University　INGEM　Assistant Professor

  • 2017/07 - 2018/03
    RIKEN　AIP　Research Scientist

  • 2009/11 - 2017/06
    RIKEN　QBiC

  • 2006/04 - 2009/03
    日本学術振興会　特別研究員(DC1)

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Education 1

  • 東京大学大学院　理学系研究科　生物化学専攻

    2004/04 - 2009/10

Professional Memberships 1

  • 日本メディカルAI学会

Research Interests 12

  • Next Generation Sequence

  • Bioinformatics

  • Genome

  • Genetic Epidemiology

  • Quantitative Genetics

  • Population Genetics

  • Statistical Genetics

  • Human Genetics

  • image processing

  • simulation

  • live imaging

  • C. elegans

Research Areas 2

  • Life sciences / Systems genomics /

  • Life sciences / Genomics /

Awards 5

  1. 日本医療研究開発機構理事長賞

    2020/01　日本医療研究開発機構　「日本人基準ゲノム配列」初版JG1の作成・公開

  2. 第8回 理研研究奨励賞

    2017/03　理化学研究所

  3. 理研CDBリトリート Best Presentation Award (Bronze)

    2015/09

  4. Poster Award in Nara Worm Meeting

    2014/07

  5. Poster award in RIKEN CDB retreat

    2012/09

Papers 50

  1. A fine-scale genetic map of the Japanese population. International-journal

    Jun Takayama, Satoshi Makino, Takamitsu Funayama, Masao Ueki, Akira Narita, Keiko Murakami, Masatsugu Orui, Mami Ishikuro, Taku Obara, Shinichi Kuriyama, Masayuki Yamamoto, Gen Tamiya

    Clinical genetics　2024/05/08

    DOI： 10.1111/cge.14536 　

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    Genetic maps are fundamental resources for linkage and association studies. A fine-scale genetic map can be constructed by inferring historical recombination events from the genome-wide structure of linkage disequilibrium-a non-random association of alleles among loci-by using population-scale sequencing data. We constructed a fine-scale genetic map and identified recombination hotspots from 10 092 551 bi-allelic high-quality autosomal markers segregating among 150 unrelated Japanese individuals whose genotypes were determined by high-coverage (30×) whole-genome sequencing, and the genotype quality was carefully controlled by using their parents' and offspring's genotypes. The pedigree information was also utilized for haplotype phasing. The resulting genome-wide recombination rate profiles were concordant with those of the worldwide population on a broad scale, and the resolution was much improved. We identified 9487 recombination hotspots and confirmed the enrichment of previously known motifs in the hotspots. Moreover, we demonstrated that the Japanese genetic map improved the haplotype phasing and genotype imputation accuracy for the Japanese population. The construction of a population-specific genetic map will help make genetics research more accurate.

  2. Functional variants in a TTTG microsatellite on 15q26.1 cause familial nonautoimmune thyroid abnormalities. International-journal

    Satoshi Narumi, Keisuke Nagasaki, Mitsuo Kiriya, Erika Uehara, Kazuhisa Akiba, Kanako Tanase-Nakao, Kazuhiro Shimura, Kiyomi Abe, Chiho Sugisawa, Tomohiro Ishii, Kenichi Miyako, Yukihiro Hasegawa, Yoshihiro Maruo, Koji Muroya, Natsuko Watanabe, Eijun Nishihara, Yuka Ito, Takahiko Kogai, Kaori Kameyama, Kazuhiko Nakabayashi, Kenichiro Hata, Maki Fukami, Hirohito Shima, Atsuo Kikuchi, Jun Takayama, Gen Tamiya, Tomonobu Hasegawa

    Nature genetics　2024/05/07

    DOI： 10.1038/s41588-024-01735-5 　

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    Insufficient thyroid hormone production in newborns is referred to as congenital hypothyroidism. Multinodular goiter (MNG), characterized by an enlarged thyroid gland with multiple nodules, is usually seen in adults and is recognized as a separate disorder from congenital hypothyroidism. Here we performed a linkage analysis of a family with both nongoitrous congenital hypothyroidism and MNG and identified a signal at 15q26.1. Follow-up analyses with whole-genome sequencing and genetic screening in congenital hypothyroidism and MNG cohorts showed that changes in a noncoding TTTG microsatellite on 15q26.1 were frequently observed in congenital hypothyroidism (137 in 989) and MNG (3 in 33) compared with controls (3 in 38,722). Characterization of the noncoding variants with epigenomic data and in vitro experiments suggested that the microsatellite is located in a thyroid-specific transcriptional repressor, and its activity is disrupted by the variants. Collectively, we presented genetic evidence linking nongoitrous congenital hypothyroidism and MNG, providing unique insights into thyroid abnormalities.

  3. Deep exome sequencing identifies enrichment of deleterious mosaic variants in neurodevelopmental disorder genes and mitochondrial tRNA regions in bipolar disorder. International-journal

    Masaki Nishioka, Jun Takayama, Naomi Sakai, An-A Kazuno, Mizuho Ishiwata, Junko Ueda, Takashi Hayama, Kumiko Fujii, Toshiyuki Someya, Shinichi Kuriyama, Gen Tamiya, Atsushi Takata, Tadafumi Kato

    Molecular psychiatry　28　(10)　4294-4306　2023/05/30

    DOI： 10.1038/s41380-023-02096-x 　

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    Bipolar disorder (BD) is a global medical issue, afflicting around 1% of the population with manic and depressive episodes. Despite various genetic studies, the genetic architecture and pathogenesis of BD have not been fully resolved. Besides germline variants, postzygotic mosaic variants are proposed as new candidate mechanisms contributing to BD. Here, we performed extensive deep exome sequencing (DES, ~300×) and validation experiments to investigate the roles of mosaic variants in BD with 235 BD cases (194 probands of trios and 41 single cases) and 39 controls. We found an enrichment of developmental disorder (DD) genes in the genes hit by deleterious mosaic variants in BD (P = 0.000552), including a ClinVar-registered pathogenic variant in ARID2. An enrichment of deleterious mosaic variants was also observed for autism spectrum disorder (ASD) genes (P = 0.000428). The proteins coded by the DD/ASD genes with non-synonymous mosaic variants in BD form more protein-protein interaction than expected, suggesting molecular mechanisms shared with DD/ASD but restricted to a subset of cells in BD. We also found significant enrichment of mitochondrial heteroplasmic variants, another class of mosaic variants, in mitochondrial tRNA genes in BD (P = 0.0102). Among them, recurrent m.3243 A > G variants known as causal for mitochondrial diseases were found in two unrelated BD probands with allele fractions of 5-12%, lower than in mitochondrial diseases. Despite the limitation of using peripheral tissues, our DES investigation supports the possible contribution of deleterious mosaic variants in the nuclear genome responsible for severer phenotypes, such as DD/ASD, to the risk of BD and further demonstrates that the same paradigm can be applied to the mitochondrial genome. These results, as well as the enrichment of heteroplasmic mitochondrial tRNA variants in BD, add a new piece to the understanding of the genetic architecture of BD and provide general insights into the pathological roles of mosaic variants in human diseases.

  4. Construction and integration of three de novo Japanese human genome assemblies toward a population-specific reference

    Jun Takayama, Shu Tadaka, Kenji Yano, Fumiki Katsuoka, Chinatsu Gocho, Takamitsu Funayama, Satoshi Makino, Yasunobu Okamura, Atsuo Kikuchi, Sachiyo Sugimoto, Junko Kawashima, Akihito Otsuki, Mika Sakurai-Yageta, Jun Yasuda, Shigeo Kure, Kengo Kinoshita, Masayuki Yamamoto, Gen Tamiya

    Nature Communications　12　(1)　2021/12

    Publisher: Springer Science and Business Media {LLC}

    DOI： 10.1038/s41467-020-20146-8 　

    eISSN： 2041-1723

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    <title>ABSTRACT</title>The complete sequence of the human genome is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the international human reference genome (e.g., GRCh37), especially Asian populations, due to a strong bias toward European and African ancestries in a single mosaic haploid genome consisting chiefly of a single donor. Here, we performed <italic>de novo</italic> assembly of the genomes from three Japanese male individuals using &gt;100× PacBio long reads and Bionano optical maps per sample. We integrated the genomes using the major allele for consensus, and anchored the scaffolds using sequence-tagged site markers from conventional genetic and radiation hybrid maps to reconstruct each chromosome sequence. The resulting genome sequence, designated JG1, is highly contiguous, accurate, and carries the major allele in the majority of single nucleotide variant sites for a Japanese population. We adopted JG1 as the reference for confirmatory exome re-analyses of seven Japanese families with rare diseases and found that re-analysis using JG1 reduced false-positive variant calls versus GRCh37 while retaining disease-causing variants. These results suggest that integrating multiple genome assemblies from a single ethnic population can aid next-generation sequencing analyses of individuals originated from the population.

  5. Profiling of runs of homozygosity from whole-genome sequence data in Japanese biobank. International-journal

    Aye Ko Ko Minn, Motomichi Matsuzaki, Akira Narita, Takamitsu Funayama, Yurii Kotsar, Satoshi Makino, Jun Takayama, Shinichi Kuriyama, Gen Tamiya

    Journal of human genetics　2025/04/03

    DOI： 10.1038/s10038-025-01331-3 　

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    Runs of homozygosity (ROHs) are widely observed across the genomes of various species and have been reported to be associated with many traits and common diseases, as well as rare recessive diseases, in human populations. Although single nucleotide polymorphism (SNP) array data have been used in previous studies on ROHs, recent advances in whole-genome sequencing (WGS) technologies and the development of nationwide cohorts/biobanks are making high-density genomic data increasingly available, and it is consequently becoming more feasible to detect ROHs at higher resolution. In the study, we searched for ROHs in two high-coverage WGS datasets from 3552 Japanese individuals and 192 three-generation families (consisting of 1120 family members) in prospective genomic cohorts. The results showed that a considerable number of ROHs, especially short ones that may have remained undetected in conventionally used SNP-array data, can be detected in the WGS data. By filtering out sequencing errors and leveraging pedigree information, longer ROHs are more likely to be detected in WGS data than in SNP-array data. Additionally, we identified gene families within ROH islands that are associated with enriched pathways related to sensory perception of taste and odors, suggesting potential signatures of selection in these key genomic regions.

  6. Idiopathic infantile hypercalcemia with a CYP24A1 variant triggered by vitamin D supplementation in fortified milk: A case report.

    Sota Iwafuchi, Nao Uchida, Naoya Saijo, Chisumi Sogi, Miki Kamimura, Jun Takayama, Gen Tamiya, Atsuo Kikuchi, Junko Kanno

    Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology　34　(1)　60-65　2025/01

    DOI： 10.1297/cpe.2024-0049 　

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    Idiopathic infantile hypercalcemia (IIH) is characterized by hypercalcemia, nephrocalcinosis, vomiting, dehydration, and failure to thrive. It is caused by the presence of biallelic loss-of-function variants in the CYP24A1 locus. Although hypercalcemia has been linked to the consumption of vitamin D-fortified milk, no reports have documented its role in triggering IIH in patients with CYP24A1 variants. Herein, we describe a case of IIH triggered by vitamin D-fortified milk consumption in a 9-mo-old male patient carrying a CYP24A1 variant. After BCG vaccination, the patient developed a facial rash, became anorexic, appeared to be in a bad mood, and began consuming vitamin D-fortified milk instead of baby food. Blood tests showed a marked hypercalcemia (18.5 mg/dL), high 1,25-(OH)2D (98.7 pg/dL) levels, and low parathyroid hormone (PTH) (< 4.0 pg/dL) and PTHrP (< 1.0 pg/dL) levels. The calcium levels were successfully normalized after treatment with saline loading, furosemide, pamidronate, and a low-calcium milk diet. After discharge, blood calcium levels remained normal with no recurrence of symptomatic hypercalcemia, but circulating PTH levels were persistently suppressed. Renal ultrasonography at 8 yr of age revealed high medullary echogenicity and diffuse echogenic foci in both kidneys. Trio-based whole-genome sequencing identified the following biallelic pathogenic variants c.[464G>A];[1324C>T], p.[Trp155Ter];[Gln442Ter], in the CYP24A1 (NM_000782.5) locus. Unexplained hypercalcemia in infants should raise suspicions of abnormal vitamin D metabolism and CYP24A1 locus genotypic analysis can be informative in this regard.

  7. Comprehensive genetic analysis for identification of monogenic disorders and selection of appropriate treatments in pediatric patients with persistent thrombocytopenia. International-journal

    Daichi Sato, Hinako Kirikae, Tomohiro Nakano, Saori Katayama, Hisao Yaoita, Jun Takayama, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi, Yoji Sasahara

    Pediatric hematology and oncology　41　(8)　541-556　2024/11

    DOI： 10.1080/08880018.2024.2395358 　

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    Persistent thrombocytopenia is caused by various diseases, including immune thrombocytopenia, inherited thrombocytopenia, and inherited bone marrow failure syndromes. Considering the large number of genes responsible for inherited disorders, comprehensive genetic analysis is required to diagnose monogenic disorders. In this study, we enrolled 53 pediatric patients with persistent thrombocytopenia exhibiting visually small or normal-sized platelets. We performed whole-exome sequencing, including 56 genes responsible for inherited thrombocytopenia, and evaluated clinical parameters according to disease type. Among 53 patients, 12 patients (22.6%) were diagnosed with monogenic disorders. Nine patients had a family history of thrombocytopenia. Pathogenic or novel variants of genes responsible for inherited thrombocytopenia were identified in three and six patients, respectively. The variants in genes for inherited thrombocytopenia with large or giant platelets were unexpectedly identified in six patients. Pathogenic variants in genes for inherited bone marrow failure syndromes with systemic features were identified in three patients with atypical symptoms. Since the definitive diagnostic methods for immune thrombocytopenia are limited, and a substantial number of patients with inherited thrombocytopenia are at a high risk of developing malignancies, comprehensive genetic analysis is indispensable for selecting appropriate therapies, avoidance of unnecessary treatments for immune thrombocytopenia, and long-term follow-up of patients with inherited thrombocytopenia.

  8. Next-generation sequencing analysis with a population-specific human reference genome.

    Tomohisa Suzuki, Kota Ninomiya, Takamitsu Funayama, Yasunobu Okamura, Shu Tadaka, Kengo Kinoshita, Masayuki Yamamoto, Shigeo Kure, Atsuo Kikuchi, Gen Tamiya, Jun Takayama

    Genes & genetic systems　2024/10/28

    DOI： 10.1266/ggs.24-00112 　

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    Next-generation sequencing (NGS) has become widely available and is routinely used in basic research and clinical practice. The reference genome sequence is an essential resource for NGS analysis, and several population-specific reference genomes have recently been constructed to provide a choice to deal with the vast genetic diversity of human samples. However, resources supporting population-specific references are insufficient, and it is burdensome to perform analysis using these reference genomes. Here, we constructed a set of resources to support NGS analysis using the Japanese reference genome, JG. We created resources for variant calling, variant-effect prediction, gene and repeat element annotations, read mappability, and RNA-seq analysis. We also provide a resource for reference coordinate conversion for further annotation enrichment. We then provide a variant calling protocol with JG. Our resources provide a guide to prepare sufficient resources for the use of population-specific reference genomes and can facilitate the migration of reference genomes.

  9. A Prevalent TMEM260 Deletion Causes Conotruncal Heart Defects, Including Truncus Arteriosus. International-journal

    Naoya Saijo, Hisao Yaoita, Jun Takayama, Chiharu Ota, Eiichiro Kawai, Masato Kimura, Akira Ozawa, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi

    American journal of medical genetics. Part A　e63906　2024/10/19

    DOI： 10.1002/ajmg.a.63906 　

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    Conotruncal heart defects are severe congenital malformations of the outflow tract, including truncus arteriosus (TA) and double-outlet right ventricle (DORV). TA is a severe congenital heart disease (CHD) in which the main arterial outflow tract of the heart fails to separate. We recently reported TMEM260 (NM_017799.4), c.1617del (p.Trp539Cysfs*9), as a major cause of TA in the Japanese population (TMEM260 Keio-Tohoku variant) comparable to the prevalence of the 22q11.2 deletion syndrome, which accounts for 12%-35% of TA. However, no other major causes of TA have not been identified. Here, we report a family that included a TA patient and a DORV patient, harboring the compound heterozygous variants of TMEM260, a 7066-bp deletion encompassing exons 6-7 and c.1393C > T, p.(Gln465*). The allele frequency of the 7066-bp deletion was particularly high in the Japanese population (0.17%). Based on the allele frequency of this deletion and c.1617del (0.36%) in the Japanese population, TMEM260 variants might be associated with more than half of the Japanese patients with TA. This study showed that TMEM260 pathogenic variants might be the most common cause of TA in the Japanese population and could explain the wide spectrum of phenotypes associated with TMEM260-related CHD, including DORV, demonstrating the usefulness of genetic testing in Japanese patients with TA.

  10. Long‐term clinical observation of patients with heterozygous <scp>KIF1A</scp> variants

    Aritomo Kawashima, Kaori Kodama, Yukimune Okubo, Wakaba Endo, Takehiko Inui, Miki Ikeda, Yu Katata, Noriko Togashi, Chihiro Ohba, Eri Imagawa, Kazuhiro Iwama, Takeshi Mizuguchi, Masahiro Kitami, Yu Aihara, Jun Takayama, Gen Tamiya, Atsuo Kikuchi, Shigeo Kure, Hirotomo Saitsu, Naomichi Matsumoto, Kazuhiro Haginoya

    American Journal of Medical Genetics Part A　2024/05/17

    Publisher: Wiley

    DOI： 10.1002/ajmg.a.63656 　

    ISSN： 1552-4825

    eISSN： 1552-4833

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    Abstract KIF1A‐related disorders (KRDs) encompass recessive and dominant variants with wide clinical variability. Recent genetic investigations have expanded the clinical phenotypes of heterozygous KIF1A variants. However, there have been a few long‐term observational studies of patients with heterozygous KIF1A variants. A retrospective chart review of consecutive patients diagnosed with spastic paraplegia at Miyagi Children's Hospital from 2016 to 2020 identified six patients with heterozygous KIF1A variants. To understand the long‐term changes in clinical symptoms, we examined these patients in terms of their characteristics, clinical symptoms, results of electrophysiological and neuroimaging studies, and genetic testing. The median follow‐up period was 30 years (4–44 years). This long‐term observational study showed that early developmental delay and equinus gait, or unsteady gait, are the first signs of disease onset, appearing with the commencement of independent walking. In addition, later age‐related progression was observed in spastic paraplegia, and the appearance of axonal neuropathy and reduced visual acuity were characteristic features of the late disease phenotype. Brain imaging showed age‐related progression of cerebellar atrophy and the appearance of hyperintensity of optic radiation on T2WI and FLAIR imaging. Long‐term follow‐up revealed a pattern of steady progression and a variety of clinical symptoms, including spastic paraplegia, peripheral neuropathy, reduced visual acuity, and some degree of cerebellar ataxia. Clinical variability between patients was observed to some extent, and therefore, further studies are required to determine the phenotype–genotype correlation.

  11. Correction: Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population. International-journal

    Hisao Yaoita, Eiichiro Kawai, Jun Takayama, Shinya Iwasawa, Naoya Saijo, Masayuki Abiko, Kouta Suzuki, Masato Kimura, Akira Ozawa, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi

    Journal of human genetics　69　(5)　185-185　2024/05

    DOI： 10.1038/s10038-024-01245-6 　

  12. CACNA1D遺伝子バリアントを同定した難治てんかんの一例

    宇根岡 紗希, 後藤 悠輔, 西條 直也, 竹澤 祐介, 植松 有里佳, 植松 貢, 浅見 麻耶, 水間 加奈子, 谷藤 幸子, 赤坂 真奈美, 高山 順, 田宮 元, 呉 繁夫, 菊池 敦生

    脳と発達　56　(Suppl.)　S312-S312　2024/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

    eISSN： 1884-7668

  13. X染色体の不活化の強い偏りにより,既報よりも重症なDEE-SWASをきたしたCNKSR2遺伝子異常の女児例

    堅田 有宇, 大久保 幸宗, 中村 晴彦, 西條 直也, 高山 順, 呉 繁夫, 田宮 元, 菊池 敦生

    脳と発達　56　(Suppl.)　S312-S312　2024/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

    eISSN： 1884-7668

  14. 神経セロイドリポフスチン症2型(CLN2)との鑑別を有した発達性てんかん性脳症91型(DEE91)の1例

    渋谷 守栄, 中村 晴彦, 西條 直也, 宇根岡 紗希, 竹澤 祐介, 及川 善嗣, 植松 有里佳, 植松 貢, 高山 順, 呉 繁雄, 田宮 元, 菊池 敦生

    脳と発達　56　(Suppl.)　S313-S313　2024/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

    eISSN： 1884-7668

  15. ロングリードシークエンス技術と集団ゲノム解析 Invited

    高山 順

    医学のあゆみ　288　(13)　1057-1062　2024/03

    DOI： 10.32118/ayu288131057 　

  16. Genetic etiology of truncus arteriosus excluding 22q11.2 deletion syndrome and identification of c.1617del, a prevalent variant in TMEM260, in the Japanese population. International-journal

    Hisao Yaoita, Eiichiro Kawai, Jun Takayama, Shinya Iwasawa, Naoya Saijo, Masayuki Abiko, Kouta Suzuki, Masato Kimura, Akira Ozawa, Gen Tamiya, Shigeo Kure, Atsuo Kikuchi

    Journal of human genetics　69　(5)　177-183　2024/02/13

    DOI： 10.1038/s10038-024-01223-y 　

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    Truncus Arteriosus (TA) is a congenital heart disease characterized by a single common blood vessel emerging from the right and left ventricles instead of the main pulmonary artery and aorta. TA accounts for 4% of all critical congenital heart diseases. The most common cause of TA is 22q11.2 deletion syndrome, accounting for 12-35% of all TA cases. However, no major causes of TA other than 22q11.2 deletion have been reported. We performed whole-genome sequencing of 11 Japanese patients having TA without 22q11.2 deletion. Among five patients, we identified pathogenic variants in TMEM260; the biallelic loss-of-function variants of which have recently been associated with structural heart defects and renal anomalies syndrome (SHDRA). In one patient, we identified a de novo pathogenic variant in GATA6, and in another patient, we identified a de novo probably pathogenic variant in NOTCH1. Notably, we identified a prevalent variant in TMEM260 (ENST00000261556.6), c.1617del (p.Trp539Cysfs*9), in 8/22 alleles among the 11 patients. The c.1617del variant was estimated to occur approximately 23 kiloyears ago. Based on the allele frequency of the c.1617del variant in the Japanese population (0.36%), approximately 26% of Japanese patients afflicted with TA could harbor homozygous c.1617del variants. This study highlights TMEM260, especially c.1617del, as a major genetic cause of TA in the Japanese population.

  17. 胎児不整脈から胎児水腫を発症し全ゲノム解析により迅速に先天性QT延長症候群と診断し得た一例

    長尾 江里菜, 小林 正久, 田邊 行敏, 馬場 俊輔, 角皆 季樹, 大石 公彦, 西城 直也, 高山 順, 菊池 敦生

    日本小児科学会雑誌　128　(2)　397-397　2024/02

    Publisher: (公社)日本小児科学会

    ISSN： 0001-6543

  18. Treatment of ZC4H2 Variant-Associated Spastic Paraplegia with Selective Dorsal Rhizotomy and Intensive Postoperative Rehabilitation: A Case Report.

    Toshiki Inotani, Akira Horaguchi, Yuko Morishita, Ayuko Yoshida, Misaki Otomo, Makoto Suzuki, Takehiko Inui, Yukimune Okubo, Shigemasa Komatsu, Chika Mizuno, Yuko Takahashi, Tatsuhiro Ochiai, Takeshi Kinjo, Takashi Asato, Jun Takayama, Gen Tamiya, Naoya Saijo, Atsuo Kikuchi, Kazuhiro Haginoya

    The Tohoku journal of experimental medicine　262　(4)　239-244　2024/01/25

    DOI： 10.1620/tjem.2024.J004 　

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    Selective dorsal rhizotomy (SDR) has been used to treat children with spastic cerebral palsy (CP), and its beneficial effect on quality of life and ambulation has been confirmed in long-term follow-up studies. However, the role of SDR in the treatment of spasticity in patients with hereditary spastic paraplegia (HSP) and related disorders is not well-established. Here, we report the first patient with the ZC4H2 variant who underwent SDR to treat spastic paraplegia. Abnormal gait was discovered during a regular checkup at the age of 3 years and 9 months, and she was diagnosed with spastic paraplegia. She was heterozygous for the ZC4H2 variant and underwent SDR at the age of 5 years and 11 months, which alleviated the spasticity. The patient underwent inpatient postoperative rehabilitation for 4 months and continued outpatient physiotherapy after discharge. The Gross Motor Function Measure-88 score and maximum walking speed decreased transiently 1 month postoperatively, but gradually recovered, and continuously improved 6 months postoperatively. SDR and postoperative intensive rehabilitation were effective in improving motor and walking functions up to 6 months after surgery, although long-term follow-up is needed to draw conclusions.

  19. Next-generation sequencing analysis with a population-specific human reference genome

    Tomohisa Suzuki, Kota Ninomiya, Takamitsu Funayama, Yasunobu Okamura, Shu Tadaka, Kengo Kinoshita, Masayuki Yamamoto, Shigeo Kure, Atsuo Kikuchi, Gen Tamiya, Jun Takayama

    Genes &amp; Genetic Systems　2024

    Publisher: Genetics Society of Japan

    DOI： 10.1266/ggs.24-00112 　

    ISSN： 1341-7568

    eISSN： 1880-5779

  20. Case Report: Identification of a CARD8 variant in all three patients with PFAPA syndrome complicated with Kawasaki disease. International-journal

    Haruhiko Nakamura, Atsuo Kikuchi, Hideyuki Sakai, Miki Kamimura, Yohei Watanabe, Ryoichi Onuma, Jun Takayama, Gen Tamiya, Yoichi Mashimo, Ryota Ebata, Hiromichi Hamada, Tomohiro Suenaga, Yoshihiro Onouchi, Satoru Kumaki

    Frontiers in pediatrics　12　1340263-1340263　2024

    DOI： 10.3389/fped.2024.1340263 　

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    BACKGROUND: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA syndrome), and Kawasaki disease (KD) are both considered to be disorders of the innate immune system, and the potential role of inflammasome activation in the immunopathogenesis of both diseases has been previously described. CASE PRESENTATION: Herein, we report the clinical courses of three patients who presented a rare combination of PFAPA syndrome and KD. Two patients who presented KD later developed the PFAPA syndrome, of whom one developed recurrent KD 2 years after the initial diagnosis. The third patient developed KD one year after the onset of PFAPA syndrome. The presence of both of these conditions within individual patients, combined with the knowledge that inflammasome activation is involved in both PFAPA syndrome and KD, suggests a shared background of inflammatory dysregulation. To elucidate the mechanism underlying shared inflammatory dysregulation, we investigated the roles of Nod-like receptors (NLRs) and their downstream inflammasome-related genes. All the patients had a frameshift variant in CARD8 (CARD8-FS). A previous study demonstrated a higher frequency of CARD8-FS, whose product loses CARD8 activity and activates the NLRP3 inflammasome, in patients with the PFAPA syndrome. Additionally, the NLRP3 inflammasome is known to be activated in patients with KD. Together, these results suggest that the CARD8-FS variant may also be essential in KD pathogenesis. As such, we analyzed the CARD8 variants among patients with KD. However, we found no difference in the variant frequency between patients with KD and the general Japanese population. CONCLUSIONS: We report the clinical courses of three patients with a rare combination of PFAPA syndrome and KD. All the patients had the CARD8-FS variant. However, we could not find a difference in the variant frequency between patients with KD and the general Japanese population. As the frequency of KD is much higher than that of PFAPA among Japanese patients, and the cause of KD is multifactorial, it is possible that only a small portion of patients with KD harbor CARD8-FS as a causative gene.

  21. jMorp: Japanese Multi-Omics Reference Panel update report 2023. International-journal

    Shu Tadaka, Junko Kawashima, Eiji Hishinuma, Sakae Saito, Yasunobu Okamura, Akihito Otsuki, Kaname Kojima, Shohei Komaki, Yuichi Aoki, Takanari Kanno, Daisuke Saigusa, Jin Inoue, Matsuyuki Shirota, Jun Takayama, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Ritsuko Shimizu, Masahiro Hiratsuka, Ikuko N Motoike, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic acids research　52　(D1)　D622-D632　2023/11/01

    DOI： 10.1093/nar/gkad978 　

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    Modern medicine is increasingly focused on personalized medicine, and multi-omics data is crucial in understanding biological phenomena and disease mechanisms. Each ethnic group has its unique genetic background with specific genomic variations influencing disease risk and drug response. Therefore, multi-omics data from specific ethnic populations are essential for the effective implementation of personalized medicine. Various prospective cohort studies, such as the UK Biobank, All of Us and Lifelines, have been conducted worldwide. The Tohoku Medical Megabank project was initiated after the Great East Japan Earthquake in 2011. It collects biological specimens and conducts genome and omics analyses to build a basis for personalized medicine. Summary statistical data from these analyses are available in the jMorp web database (https://jmorp.megabank.tohoku.ac.jp), which provides a multidimensional approach to the diversity of the Japanese population. jMorp was launched in 2015 as a public database for plasma metabolome and proteome analyses and has been continuously updated. The current update will significantly expand the scale of the data (metabolome, genome, transcriptome, and metagenome). In addition, the user interface and backend server implementations were rewritten to improve the connectivity between the items stored in jMorp. This paper provides an overview of the new version of the jMorp.

  22. A Case Series of Patients With MYBPC1 Gene Variants Featuring Undulating Tongue Movements as Myogenic Tremor International-journal

    Saki Uneoka, Tomoko Kobayashi, Yurika Numata-Uematsu, Yoshitsugu Oikawa, Yu Katata, Yukimune Okubo, Yu Abe, Atsuo Kikuchi, Jun Takayama, Gen Tamiya, Shigeo Kure, Kayoko Saito, Mitsugu Uematsu

    Pediatric Neurology　146　16-20　2023/09

    Publisher: Elsevier BV

    DOI： 10.1016/j.pediatrneurol.2023.06.002 　

    ISSN： 0887-8994

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    Myosin-binding protein C1 (MYBPC1) encodes myosin-binding protein C, slow type (sMyBP-C), an accessory protein that regulates actomyosin cross-linking, stabilizes thick filaments, and modulates contractility in muscle sarcomeres and has recently been linked to myopathy with tremor. The clinical features of MYBPC1 mutations manifesting in early childhood bear some similarities to those of spinal muscular atrophy (SMA), such as hypotonia, involuntary movement of the tongue and limbs, and delayed motor development. The development of novel therapies for SMA has necessitated the importance of differentiating SMA from other diseases in the early infancy period. We report the characteristic tongue movements of MYBPC1 mutations, along with other clinical findings, such as positive deep tendon reflexes and normal peripheral nerve conduction velocity testing, which could help in considering other diseases as differential diagnoses.

  23. 双極性障害における体細胞変異の役割

    西岡 将基, 高山 順, 酒井 直美, 数野 安亜, 石渡 みずほ, 林 順子, 早馬 俊, 藤井 久彌子, 染矢 俊幸, 栗山 進一, 田宮 元, 高田 篤, 加藤 忠史

    精神神経学雑誌　(2023特別号)　S404-S404　2023/06

    Publisher: (公社)日本精神神経学会

    ISSN： 0033-2658

  24. PBX1遺伝子異常の家系を有するOligomeganephroniaの男子例

    津川 浩二, 佐藤 理子, 橋本 峻, 藤田 真司, 相澤 知美, 照井 君典, 菊池 敦生, 高山 順, 田中 完

    日本小児腎臓病学会雑誌　36　(Suppl.)　190-190　2023/05

    Publisher: (一社)日本小児腎臓病学会

    ISSN： 0915-2245

    eISSN： 1881-3933

  25. 特徴的な表出性言語障害を伴うSETBP1 Haploinsufficiency Disorderの1例

    阿部 裕, 菊池 敦生, 石川 純大, 篠原 健, 新井 啓, 佐藤 聖子, 佐藤 紘一, 齋藤 なか, 吉田 宏, 高山 順, 田宮 元, 呉 繁夫

    脳と発達　55　(Suppl.)　S408-S408　2023/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

    eISSN： 1884-7668

  26. DXの社会実装 医療全般におけるDXの現状

    仁宮 洸太, 高山 順, 田宮 元

    肝胆膵　86　(2)　129-138　2023/02

  27. Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis. International-journal

    Stavroula Kanoni, Sarah E Graham, Yuxuan Wang, Ida Surakka, Shweta Ramdas, Xiang Zhu, Shoa L Clarke, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Greg J M Zajac, Kuan-Han H Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M Brumpton, Humaira Rasheed, Aki S Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J Kullo, Akira Narita, Jun Takayama, Hilary C Martin, Karen A Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E Miller, Archie Campbell, Kuang Lin, Iona Y Millwood, Asif Rasheed, George Hindy, Jessica D Faul, Wei Zhao, David R Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R Brown, Weihua Zhang, Ketian Yu, Ellen M Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian'an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R Wood, Yingji Ji, Zishan Gao, Simon Haworth, Noha A Yousri, Ruth E Mitchell, Jin Fang Chai, Mette Aadahl, Anne A Bjerregaard, Jie Yao, Ani Manichaikul, Chii-Min Hwu, Yi-Jen Hung, Helen R Warren, Julia Ramirez, Jette Bork-Jensen, Line L Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Claudia Lamina, Lukas Forer, Markus Scholz, Tessel E Galesloot, Jonathan P Bradfield, Sanni E Ruotsalainen, EWarwick Daw, Joseph M Zmuda, Jonathan S Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A Brody, Miguel Vazquez-Moreno, Mary F Feitosa, Mary K Wojczynski, Zhe Wang, Michael H Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W Benjamins, Jorgen Engmann, Noah L Tsao, Anurag Verma, Roderick C Slieker, Ken Sin Lo, Nuno R Zilhao, Phuong Le, Marcus E Kleber, Graciela E Delgado, Shaofeng Huo, Daisuke D Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L Leonard, Jonathan Marten, Mirjam Frank, Börge Schmidt, Laura J Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S Nongmaithem, Swati Bayyana, Heather M Stringham, Marguerite R Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R H J Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C Warner, Ya Xing Wang, Wen B Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A Kentistou, Bernhard Banas, Giuseppe Giovanni Nardone, Karina Meidtner, Lawrence F Bielak, Jennifer A Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J van der Most, Niina Pitkänen, Brian E Cade, Sander W van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R Bentley, Ayo P Doumatey, Adebowale A Adeyemo, Jong Young Lee, Eva R B Petersen, Aneta A Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W Rayner, Carol A Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O Obura, Jessica van Setten, Xiaoyin Li, Jingjing Liang, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D Jackson, Alexander P Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C Bis, Lenore J Launer, Huaixing Li, Mike A Nalls, Olli T Raitakari, Sahoko Ichihara, Sarah H Wild, Christopher P Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J de Borst, Eung Kweon Kim, Hieab H H Adams, M Arfan Ikram, Xiaofeng Zhu, Folkert W Asselbergs, Adriaan O Kraaijeveld, Joline W J Beulens, Xiao-Ou Shu, Loukianos S Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E Pennell, Trevor A Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M Heid, Klaus J Stark, Martina E Zimmermann, Henry Völzke, Georg Homuth, Michele K Evans, Alan B Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E Hoefer, Susan Redline, Katja Pahkala, Albertine J Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Sharon L R Kardia, Patricia A Peyser, Norihiro Kato, Matthias B Schulze, Giorgia Girotto, Carsten A Böger, Bettina Jung, Peter K Joshi, David A Bennett, Philip L De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J Caulfield, Patricia B Munroe, Xiuqing Guo, Marina Ciullo, Jost B Jonas, Nilesh J Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Linda S Adair, Sonny Augustin Bechayda, H Janaka de Silva, Ananda R Wickremasinghe, Ronald M Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke Iden Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G Wilson, Lars Lind, Chew-Kiat Heng, Amanda E Nelson, Yvonne M Golightly, James F Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J Scott, D C Rao, Donna K Arnett, Steven C Hunt, Mark Walker, Heikki A Koistinen, Giriraj R Chandak, Josep M Mercader, Maria C Costanzo, Dongkeun Jang, Noël P Burtt, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, EShyong Tai, Rob M van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I McCarthy, Colin N A Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M van Duijn, Zi-Bing Jin, Jia Qu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M 't Hart, Petra J M Elders, Scott M Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D Spector, Ruth J F Loos, Michael A Province, Esteban J Parra, Miguel Cruz, Bruce M Psaty, Ivan Brandslund, Peter P Pramstaller, Charles N Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F A Grant, Lambertus A L M Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W Franks, Allan Linneberg, J Wouter Jukema, Amit V Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P Strachan, Niels Grarup, Peter Sever, Neil Poulter, Lee-Ming Chuang, Jerome I Rotter, Thomas M Dantoft, Fredrik Karpe, Matt J Neville, Nicholas J Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T Hattersley, Nancy L Pedersen, Patrik K E Magnusson, Dorret I Boomsma, Allegonda H M Willemsen, LAdrienne Cupples, Joyce B J van Meurs, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J Wareham, Claudia Langenberg, Eleftheria Zeggini, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C Chambers, Jaspal S Kooner, Paul S de Vries, Alanna C Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E North, Martha Daviglus, Peter Kraft, Nicholas G Martin, John B Whitfield, Shahid Abbas, Danish Saleheen, Robin G Walters, Michael V Holmes, Corri Black, Blair H Smith, Aris Baras, Anne E Justice, Julie E Buring, Paul M Ridker, Daniel I Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A van Heel, Richard C Trembath, Wei-Qi Wei, Gail P Jarvik, Bahram Namjou, M Geoffrey Hayes, Marylyn D Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, YEugene Chen, Yuk-Lam Ho, Julie A Lynch, Daniel J Rader, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, John M Gaziano, Peter W F Wilson, Timothy M Frayling, Joel N Hirschhorn, Sekar Kathiresan, Karen L Mohlke, Yan V Sun, Andrew P Morris, Michael Boehnke, Christopher D Brown, Pradeep Natarajan, Panos Deloukas, Cristen J Willer, Themistocles L Assimes, Gina M Peloso

    Genome biology　23　(1)　268-268　2022/12/27

    DOI： 10.1186/s13059-022-02837-1 　

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    BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.

  28. Familial Paget's disease of bone with ocular manifestations and a novel TNFRSF11A duplication variant (72dup27).

    Akiko Saito-Hakoda, Atsuo Kikuchi, Tadahisa Takahashi, Yu Yokoyama, Noriko Himori, Mika Adachi, Ryoukichi Ikeda, Yuri Nomura, Jun Takayama, Junko Kawashima, Fumiki Katsuoka, Fumiyoshi Fujishima, Takehiko Yamaguchi, Akiyo Ito, Takushi Hanita, Junko Kanno, Toshimi Aizawa, Toru Nakazawa, Tetsuaki Kawase, Gen Tamiya, Masayuki Yamamoto, Ikuma Fujiwara, Shigeo Kure

    Journal of bone and mineral metabolism　41　(2)　193-202　2022/12/15

    DOI： 10.1007/s00774-022-01392-w 　

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    INTRODUCTION: Paget's disease of bone (PDB) is a skeletal disorder characterized by disorganized bone remodeling due to abnormal osteoclasts. Tumor necrosis factor receptor superfamily member 11A (TNFRSF11A) gene encodes the receptor activator of nuclear factor kappa B (RANK), which has a critical role in osteoclast function. There are five types of rare PDB and related osteolytic disorders due to TNFRSF11A tandem duplication variants so far, including familial expansile osteolysis (84dup18), expansile skeletal hyperphosphatasia (84dup15), early-onset familial PDB (77dup27), juvenile PDB (87dup15), and panostotic expansile bone disease (90dup12). MATERIALS AND METHODS: We reviewed a Japanese family with PDB, and performed whole-genome sequencing to identify a causative variant. RESULTS: This family had bone symptoms, hyperphosphatasia, hearing loss, tooth loss, and ocular manifestations such as angioid streaks or early-onset glaucoma. We identified a novel duplication variant of TNFRSF11A (72dup27). Angioid streaks were recognized in Juvenile Paget's disease due to loss-of-function variants in the gene TNFRSF11B, and thought to be specific for this disease. However, the novel recognition of angioid streaks in our family raised the possibility of occurrence even in bone disorders due to TNFRSF11A duplication variants and the association of RANKL-RANK signal pathway as the pathogenesis. Glaucoma has conversely not been reported in any case of Paget's disease. It is not certain whether glaucoma is coincidental or specific for PDB with 72dup27. CONCLUSION: Our new findings might suggest a broad spectrum of phenotypes in bone disorders with TNFRSF11A duplication variants.

  29. Construction of a trio-based structural variation panel utilizing activated T lymphocytes and long-read sequencing technology. International-journal

    Akihito Otsuki, Yasunobu Okamura, Noriko Ishida, Shu Tadaka, Jun Takayama, Kazuki Kumada, Junko Kawashima, Keiko Taguchi, Naoko Minegishi, Shinichi Kuriyama, Gen Tamiya, Kengo Kinoshita, Fumiki Katsuoka, Masayuki Yamamoto

    Communications biology　5　(1)　991-991　2022/09/20

    DOI： 10.1038/s42003-022-03953-1 　

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    Long-read sequencing technology enable better characterization of structural variants (SVs). To adapt the technology to population-scale analyses, one critical issue is to obtain sufficient amount of high-molecular-weight genomic DNA. Here, we propose utilizing activated T lymphocytes, which can be established efficiently in a biobank to stably supply high-grade genomic DNA sufficiently. We conducted nanopore sequencing of 333 individuals constituting 111 trios with high-coverage long-read sequencing data (depth 22.2x, N50 of 25.8 kb) and identified 74,201 SVs. Our trio-based analysis revealed that more than 95% of the SVs were concordant with Mendelian inheritance. We also identified SVs associated with clinical phenotypes, all of which appear to be stably transmitted from parents to offspring. Our data provide a catalog of SVs in the general Japanese population, and the applied approach using the activated T-lymphocyte resource will contribute to biobank-based human genetic studies focusing on SVs at the population scale.

  30. A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids. International-journal Peer-reviewed

    Shweta Ramdas, Jonathan Judd, Sarah E Graham, Stavroula Kanoni, Yuxuan Wang, Ida Surakka, Brandon Wenz, Shoa L Clarke, Alessandra Chesi, Andrew Wells, Konain Fatima Bhatti, Sailaja Vedantam, Thomas W Winkler, Adam E Locke, Eirini Marouli, Greg J M Zajac, Kuan-Han H Wu, Ioanna Ntalla, Qin Hui, Derek Klarin, Austin T Hilliard, Zeyuan Wang, Chao Xue, Gudmar Thorleifsson, Anna Helgadottir, Daniel F Gudbjartsson, Hilma Holm, Isleifur Olafsson, Mi Yeong Hwang, Sohee Han, Masato Akiyama, Saori Sakaue, Chikashi Terao, Masahiro Kanai, Wei Zhou, Ben M Brumpton, Humaira Rasheed, Aki S Havulinna, Yogasudha Veturi, Jennifer Allen Pacheco, Elisabeth A Rosenthal, Todd Lingren, QiPing Feng, Iftikhar J Kullo, Akira Narita, Jun Takayama, Hilary C Martin, Karen A Hunt, Bhavi Trivedi, Jeffrey Haessler, Franco Giulianini, Yuki Bradford, Jason E Miller, Archie Campbell, Kuang Lin, Iona Y Millwood, Asif Rasheed, George Hindy, Jessica D Faul, Wei Zhao, David R Weir, Constance Turman, Hongyan Huang, Mariaelisa Graff, Ananyo Choudhury, Dhriti Sengupta, Anubha Mahajan, Michael R Brown, Weihua Zhang, Ketian Yu, Ellen M Schmidt, Anita Pandit, Stefan Gustafsson, Xianyong Yin, Jian'an Luan, Jing-Hua Zhao, Fumihiko Matsuda, Hye-Mi Jang, Kyungheon Yoon, Carolina Medina-Gomez, Achilleas Pitsillides, Jouke Jan Hottenga, Andrew R Wood, Yingji Ji, Zishan Gao, Simon Haworth, Ruth E Mitchell, Jin Fang Chai, Mette Aadahl, Anne A Bjerregaard, Jie Yao, Ani Manichaikul, Wen-Jane Lee, Chao Agnes Hsiung, Helen R Warren, Julia Ramirez, Jette Bork-Jensen, Line L Kårhus, Anuj Goel, Maria Sabater-Lleal, Raymond Noordam, Pala Mauro, Floris Matteo, Aaron F McDaid, Pedro Marques-Vidal, Matthias Wielscher, Stella Trompet, Naveed Sattar, Line T Møllehave, Matthias Munz, Lingyao Zeng, Jianfeng Huang, Bin Yang, Alaitz Poveda, Azra Kurbasic, Sebastian Schönherr, Lukas Forer, Markus Scholz, Tessel E Galesloot, Jonathan P Bradfield, Sanni E Ruotsalainen, E Warwick Daw, Joseph M Zmuda, Jonathan S Mitchell, Christian Fuchsberger, Henry Christensen, Jennifer A Brody, Phuong Le, Mary F Feitosa, Mary K Wojczynski, Daiane Hemerich, Michael Preuss, Massimo Mangino, Paraskevi Christofidou, Niek Verweij, Jan W Benjamins, Jorgen Engmann, Tsao L Noah, Anurag Verma, Roderick C Slieker, Ken Sin Lo, Nuno R Zilhao, Marcus E Kleber, Graciela E Delgado, Shaofeng Huo, Daisuke D Ikeda, Hiroyuki Iha, Jian Yang, Jun Liu, Ayşe Demirkan, Hampton L Leonard, Jonathan Marten, Carina Emmel, Börge Schmidt, Laura J Smyth, Marisa Cañadas-Garre, Chaolong Wang, Masahiro Nakatochi, Andrew Wong, Nina Hutri-Kähönen, Xueling Sim, Rui Xia, Alicia Huerta-Chagoya, Juan Carlos Fernandez-Lopez, Valeriya Lyssenko, Suraj S Nongmaithem, Alagu Sankareswaran, Marguerite R Irvin, Christopher Oldmeadow, Han-Na Kim, Seungho Ryu, Paul R H J Timmers, Liubov Arbeeva, Rajkumar Dorajoo, Leslie A Lange, Gauri Prasad, Laura Lorés-Motta, Marc Pauper, Jirong Long, Xiaohui Li, Elizabeth Theusch, Fumihiko Takeuchi, Cassandra N Spracklen, Anu Loukola, Sailalitha Bollepalli, Sophie C Warner, Ya Xing Wang, Wen B Wei, Teresa Nutile, Daniela Ruggiero, Yun Ju Sung, Shufeng Chen, Fangchao Liu, Jingyun Yang, Katherine A Kentistou, Bernhard Banas, Anna Morgan, Karina Meidtner, Lawrence F Bielak, Jennifer A Smith, Prashantha Hebbar, Aliki-Eleni Farmaki, Edith Hofer, Maoxuan Lin, Maria Pina Concas, Simona Vaccargiu, Peter J van der Most, Niina Pitkänen, Brian E Cade, Sander W van der Laan, Kumaraswamy Naidu Chitrala, Stefan Weiss, Amy R Bentley, Ayo P Doumatey, Adebowale A Adeyemo, Jong Young Lee, Eva R B Petersen, Aneta A Nielsen, Hyeok Sun Choi, Maria Nethander, Sandra Freitag-Wolf, Lorraine Southam, Nigel W Rayner, Carol A Wang, Shih-Yi Lin, Jun-Sing Wang, Christian Couture, Leo-Pekka Lyytikäinen, Kjell Nikus, Gabriel Cuellar-Partida, Henrik Vestergaard, Bertha Hidalgo, Olga Giannakopoulou, Qiuyin Cai, Morgan O Obura, Jessica van Setten, Karen Y He, Hua Tang, Natalie Terzikhan, Jae Hun Shin, Rebecca D Jackson, Alexander P Reiner, Lisa Warsinger Martin, Zhengming Chen, Liming Li, Takahisa Kawaguchi, Joachim Thiery, Joshua C Bis, Lenore J Launer, Huaixing Li, Mike A Nalls, Olli T Raitakari, Sahoko Ichihara, Sarah H Wild, Christopher P Nelson, Harry Campbell, Susanne Jäger, Toru Nabika, Fahd Al-Mulla, Harri Niinikoski, Peter S Braund, Ivana Kolcic, Peter Kovacs, Tota Giardoglou, Tomohiro Katsuya, Dominique de Kleijn, Gert J de Borst, Eung Kweon Kim, Hieab H H Adams, M Arfan Ikram, Xiaofeng Zhu, Folkert W Asselbergs, Adriaan O Kraaijeveld, Joline W J Beulens, Xiao-Ou Shu, Loukianos S Rallidis, Oluf Pedersen, Torben Hansen, Paul Mitchell, Alex W Hewitt, Mika Kähönen, Louis Pérusse, Claude Bouchard, Anke Tönjes, Yii-Der Ida Chen, Craig E Pennell, Trevor A Mori, Wolfgang Lieb, Andre Franke, Claes Ohlsson, Dan Mellström, Yoon Shin Cho, Hyejin Lee, Jian-Min Yuan, Woon-Puay Koh, Sang Youl Rhee, Jeong-Taek Woo, Iris M Heid, Klaus J Stark, Martina E Zimmermann, Henry Völzke, Georg Homuth, Michele K Evans, Alan B Zonderman, Ozren Polasek, Gerard Pasterkamp, Imo E Hoefer, Susan Redline, Katja Pahkala, Albertine J Oldehinkel, Harold Snieder, Ginevra Biino, Reinhold Schmidt, Helena Schmidt, Stefania Bandinelli, George Dedoussis, Thangavel Alphonse Thanaraj, Patricia A Peyser, Norihiro Kato, Matthias B Schulze, Giorgia Girotto, Carsten A Böger, Bettina Jung, Peter K Joshi, David A Bennett, Philip L De Jager, Xiangfeng Lu, Vasiliki Mamakou, Morris Brown, Mark J Caulfield, Patricia B Munroe, Xiuqing Guo, Marina Ciullo, Jost B Jonas, Nilesh J Samani, Jaakko Kaprio, Päivi Pajukanta, Teresa Tusié-Luna, Carlos A Aguilar-Salinas, Linda S Adair, Sonny Augustin Bechayda, H Janaka de Silva, Ananda R Wickremasinghe, Ronald M Krauss, Jer-Yuarn Wu, Wei Zheng, Anneke I den Hollander, Dwaipayan Bharadwaj, Adolfo Correa, James G Wilson, Lars Lind, Chew-Kiat Heng, Amanda E Nelson, Yvonne M Golightly, James F Wilson, Brenda Penninx, Hyung-Lae Kim, John Attia, Rodney J Scott, D C Rao, Donna K Arnett, Mark Walker, Laura J Scott, Heikki A Koistinen, Giriraj R Chandak, Josep M Mercader, Clicerio Gonzalez Villalpando, Lorena Orozco, Myriam Fornage, E Shyong Tai, Rob M van Dam, Terho Lehtimäki, Nish Chaturvedi, Mitsuhiro Yokota, Jianjun Liu, Dermot F Reilly, Amy Jayne McKnight, Frank Kee, Karl-Heinz Jöckel, Mark I McCarthy, Colin N A Palmer, Veronique Vitart, Caroline Hayward, Eleanor Simonsick, Cornelia M van Duijn, Zi-Bing Jin, Fan Lu, Haretsugu Hishigaki, Xu Lin, Winfried März, Vilmundur Gudnason, Jean-Claude Tardif, Guillaume Lettre, Leen M T Hart, Petra J M Elders, Daniel J Rader, Scott M Damrauer, Meena Kumari, Mika Kivimaki, Pim van der Harst, Tim D Spector, Ruth J F Loos, Michael A Province, Esteban J Parra, Miguel Cruz, Bruce M Psaty, Ivan Brandslund, Peter P Pramstaller, Charles N Rotimi, Kaare Christensen, Samuli Ripatti, Elisabeth Widén, Hakon Hakonarson, Struan F A Grant, Lambertus Kiemeney, Jacqueline de Graaf, Markus Loeffler, Florian Kronenberg, Dongfeng Gu, Jeanette Erdmann, Heribert Schunkert, Paul W Franks, Allan Linneberg, J Wouter Jukema, Amit V Khera, Minna Männikkö, Marjo-Riitta Jarvelin, Zoltan Kutalik, Cucca Francesco, Dennis O Mook-Kanamori, Ko Willems van Dijk, Hugh Watkins, David P Strachan, Niels Grarup, Peter Sever, Neil Poulter, Wayne Huey-Herng Sheu, Jerome I Rotter, Thomas M Dantoft, Fredrik Karpe, Matt J Neville, Nicholas J Timpson, Ching-Yu Cheng, Tien-Yin Wong, Chiea Chuen Khor, Hengtong Li, Charumathi Sabanayagam, Annette Peters, Christian Gieger, Andrew T Hattersley, Nancy L Pedersen, Patrik K E Magnusson, Dorret I Boomsma, Eco J C de Geus, L Adrienne Cupples, Joyce B J van Meurs, Arfan Ikram, Mohsen Ghanbari, Penny Gordon-Larsen, Wei Huang, Young Jin Kim, Yasuharu Tabara, Nicholas J Wareham, Claudia Langenberg, Eleftheria Zeggini, Jaakko Tuomilehto, Johanna Kuusisto, Markku Laakso, Erik Ingelsson, Goncalo Abecasis, John C Chambers, Jaspal S Kooner, Paul S de Vries, Alanna C Morrison, Scott Hazelhurst, Michèle Ramsay, Kari E North, Martha Daviglus, Peter Kraft, Nicholas G Martin, John B Whitfield, Shahid Abbas, Danish Saleheen, Robin G Walters, Michael V Holmes, Corri Black, Blair H Smith, Aris Baras, Anne E Justice, Julie E Buring, Paul M Ridker, Daniel I Chasman, Charles Kooperberg, Gen Tamiya, Masayuki Yamamoto, David A van Heel, Richard C Trembath, Wei-Qi Wei, Gail P Jarvik, Bahram Namjou, M Geoffrey Hayes, Marylyn D Ritchie, Pekka Jousilahti, Veikko Salomaa, Kristian Hveem, Bjørn Olav Åsvold, Michiaki Kubo, Yoichiro Kamatani, Yukinori Okada, Yoshinori Murakami, Bong-Jo Kim, Unnur Thorsteinsdottir, Kari Stefansson, Jifeng Zhang, Y Eugene Chen, Yuk-Lam Ho, Julie A Lynch, Philip S Tsao, Kyong-Mi Chang, Kelly Cho, Christopher J O'Donnell, John M Gaziano, Peter Wilson, Karen L Mohlke, Timothy M Frayling, Joel N Hirschhorn, Sekar Kathiresan, Michael Boehnke, Struan Grant, Pradeep Natarajan, Yan V Sun, Andrew P Morris, Panos Deloukas, Gina Peloso, Themistocles L Assimes, Cristen J Willer, Xiang Zhu, Christopher D Brown

    American journal of human genetics　109　(8)　1366-1387　2022/08/04

    DOI： 10.1016/j.ajhg.2022.06.012 　

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    A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.

  31. 医療AI人材育成と医療オントロジー

    髙山 順

    月刊インナービジョン　37　(7)　2022/07

  32. ATP7A遺伝子変異はメンケス病だけでなくSMAX3の原因遺伝子でもある

    渋谷 守栄, 矢尾板 久雄, 児玉 香織, 大久保 幸宗, 遠藤 若葉, 乾 健彦, 冨樫 紀子, 高山 順, 田宮 元, 菊池 敦生, 萩野谷 和裕, 呉 繁夫

    脳と発達　54　(Suppl.)　S301-S301　2022/05

    Publisher: (一社)日本小児神経学会

    ISSN： 0029-0831

    eISSN： 1884-7668

  33. Two Siblings with Cerebellar Ataxia, Mental Retardation, and Disequilibrium Syndrome 4 and a Novel Variant of ATP8A2.

    Yuta Narishige, Hisao Yaoita, Moriei Shibuya, Miki Ikeda, Kaori Kodama, Aritomo Kawashima, Yukimune Okubo, Wakaba Endo, Takehiko Inui, Noriko Togashi, Soichiro Tanaka, Yasuko Kobayashi, Akira Onuma, Jun Takayama, Gen Tamiya, Atsuo Kikuchi, Shigeo Kure, Kazuhiro Haginoya

    The Tohoku journal of experimental medicine　256　(4)　321-326　2022/04/29

    DOI： 10.1620/tjem.2022.J010 　

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    Cerebellar ataxia, mental retardation, and disequilibrium syndrome 4 (CAMRQ4) is early onset neuromotor disorder and intellectual disabilities caused by variants of ATP8A2. We report sibling cases and systematically analyze previous literature to increase our understanding of CAMRQ4. Japanese siblings presented with athetotic movements at 1 and 2 months of age. They also had ptosis, ophthalmoplegia, feeding difficulty, hypotonia, and severely delayed development. One patient had retinal degeneration and optic atrophy. Flattening of the auditory brainstem responses and areflexia developed. At the last follow-up, neither patient could sit or achieve head control, although some nonverbal communication was preserved. Whole exome sequencing revealed compound heterozygous variants of ATP8A2: NM_016529.6:c.[1741C>T];[2158C>T] p.[(Arg581*)];[(Arg720*)]. The p.(Arg581*) variant has been reported, while the variant p.(Arg720*) was novel. The symptoms did not progress in the early period of development, which makes it difficult to distinguish from dyskinetic cerebral palsy, particularly in solitary cases. However, visual and hearing impairments associated with involuntary movements and severe developmental delay may be a clue to suspect CAMRQ4.

  34. The longest reported sibling survivors of a severe form of congenital myasthenic syndrome with the ALG14 pathogenic variant. International-journal

    Yu Katata, Saki Uneoka, Naoya Saijyo, Yu Aihara, Takamitsu Miyazoe, Shun Koyamaishi, Yoshitsugu Oikawa, Yuya Ito, Yu Abe, Yurika Numata-Uematsu, Jun Takayama, Atsuo Kikuchi, Gen Tamiya, Mitsugu Uematsu, Shigeo Kure

    American journal of medical genetics. Part A　188　(4)　1293-1298　2022/04

    DOI： 10.1002/ajmg.a.62629 　

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    Congenital myasthenic syndromes (CMS) is a group of diseases that causes abnormalities at the neuromuscular junction owing to genetic anomalies. The pathogenic variant in ALG14 results in a severe pathological form of CMS causing end-plate acetylcholine receptor deficiency. Here, we report the cases of two siblings with CMS associated with a novel variant in ALG14. Immediately after birth, they showed hypotonia and multiple joint contractures with low Apgar scores. Ptosis, low-set ears, and high-arched palate were noted. Deep tendon reflexes were symmetrical. They showed worsening swallowing and respiratory problems; hence, nasal feeding and tracheotomy were performed. Cranial magnetic resonance imaging scans revealed delayed myelination and cerebral atrophy. Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14. Repetitive nerve stimulation test showed an abnormal decrease in compound muscle action potential. After treatment with pyridostigmine, the time off the respirator increased. Their epileptic seizures were well controlled by anti-epileptic drugs. Their clinical course is stable even now at the ages of 5 and 2 years, making them the longest reported survivors of a severe form of CMS with the ALG14 variant thus far.

  35. Development of a prognostic prediction support system for cervical intraepithelial neoplasia using artificial intelligence-based diagnosis International-journal Peer-reviewed

    Takayuki Takahashi, Hikaru Matsuoka, Rieko Sakurai, Jun Akatsuka, Yusuke Kobayashi, Masaru Nakamura, Takashi Iwata, Kouji Banno, Motomichi Matsuzaki, Jun Takayama, Daisuke Aoki, Yoichiro Yamamoto, Gen Tamiya

    Journal of Gynecologic Oncology　33　(5)　e57　2022

    DOI： 10.3802/jgo.2022.33.e57 　

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    OBJECTIVE: Human papillomavirus subtypes are predictive indicators of cervical intraepithelial neoplasia (CIN) progression. While colposcopy is also an essential part of cervical cancer prevention, its accuracy and reproducibility are limited because of subjective evaluation. This study aimed to develop an artificial intelligence (AI) algorithm that can accurately detect the optimal lesion associated with prognosis using colposcopic images of CIN2 patients by utilizing objective AI diagnosis. METHODS: We identified colposcopic findings associated with the prognosis of patients with CIN2. We developed a convolutional neural network that can automatically detect the rate of high-grade lesions in the uterovaginal area in 12 segments. We finally evaluated the detection accuracy of our AI algorithm compared with the scores by multiple gynecologic oncologists. RESULTS: High-grade lesion occupancy in the uterovaginal area detected by senior colposcopists was significantly correlated with the prognosis of patients with CIN2. The detection rate for high-grade lesions in 12 segments of the uterovaginal area by the AI system was 62.1% for recall, and the overall correct response rate was 89.7%. Moreover, the percentage of high-grade lesions detected by the AI system was significantly correlated with the rate detected by multiple gynecologic senior oncologists (r=0.61). CONCLUSION: Our novel AI algorithm can accurately determine high-grade lesions associated with prognosis on colposcopic images, and these results provide an insight into the additional utility of colposcopy for the management of patients with CIN2.

  36. A patient with early-onset SMAX3 and a novel variant of ATP7A. International-journal

    Moriei Shibuya, Hisao Yaoita, Kaori Kodama, Yukimune Okubo, Wakaba Endo, Takehiko Inui, Noriko Togashi, Jun Takayama, Gen Tamiya, Atsuo Kikuchi, Shigeo Kure, Kazuhiro Haginoya

    Brain & development　44　(1)　63-67　2021/08/26

    DOI： 10.1016/j.braindev.2021.08.004 　

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    OBJECTIVE: To describe clinical and genetic studies on a patient with early-onset spinal muscular atrophyX3 (SMAX3) with novel variant of ATP7A. METHODS: Clinical, neurophysiological, neuroimaging and pathological examinations were performed. Whole exome sequencing was applied to search genetic bases of this patient. RESULTS: The patient had gait abnormality from early infantile period. Muscle imaging at 42 years old showed predominant involvement of proximal muscles as compared to the distal muscles. The patient had a novel variant of ATP7A, which was the fourth genotype of ATP7A exhibited as SMAX3. Contrary to previous reports of distal motor neuropathy, the clinical and neuroimaging findings in this case revealed dominant involvement in the proximal portion of the extremities and trunk, which is similar to patients with type III SMA. CONCLUSION: The dominant involvement of proximal motor system in this patient may expand the phenotypic variability of SMAX3. We need to be aware of this disorder in differential diagnosis of patients with type III SMA-like phenotype.

  37. C. elegans spermatozoa lacking spe-45 are incapable of fusing with the oocyte plasma membrane. International-journal

    Jun Takayama, Tatsuya Tajima, Shuichi Onami, Hitoshi Nishimura

    microPublication biology　2021　2021/02/21

    DOI： 10.17912/micropub.biology.000372 　

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    C. elegans spe-9 class genes encode sperm proteins with indispensable roles during fertilization. We have previously reported that spe-45 belongs to the spe-9 class, based on the finding that self-sperm of spe-45(tm3715) hermaphrodites were not consumed by fertilization. In this study, we directly observed live fertilization in the spermatheca of fem-1(hc17) females after mating with spe-45(tm3715) males. As expected, it was clearly shown that spe-45 mutant spermatozoa failed to fuse with the oocyte plasma membrane. Thus, our live imaging system for C. elegans fertilization seems to be useful for evaluation of the functions of male and female gametes.

  38. Statistical image processing quantifies the changes in cytoplasmic texture associated with aging in Caenorhabditis elegans oocytes. International-journal

    Momoko Imakubo, Jun Takayama, Hatsumi Okada, Shuichi Onami

    BMC bioinformatics　22　(1)　73-73　2021/02/17

    DOI： 10.1186/s12859-021-03990-3 　

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    BACKGROUND: Oocyte quality decreases with aging, thereby increasing errors in fertilization, chromosome segregation, and embryonic cleavage. Oocyte appearance also changes with aging, suggesting a functional relationship between oocyte quality and appearance. However, no methods are available to objectively quantify age-associated changes in oocyte appearance. RESULTS: We show that statistical image processing of Nomarski differential interference contrast microscopy images can be used to quantify age-associated changes in oocyte appearance in the nematode Caenorhabditis elegans. Max-min value (mean difference between the maximum and minimum intensities within each moving window) quantitatively characterized the difference in oocyte cytoplasmic texture between 1- and 3-day-old adults (Day 1 and Day 3 oocytes, respectively). With an appropriate parameter set, the gray level co-occurrence matrix (GLCM)-based texture feature Correlation (COR) more sensitively characterized this difference than the Max-min Value. Manipulating the smoothness of and/or adding irregular structures to the cytoplasmic texture of Day 1 oocyte images reproduced the difference in Max-min Value but not in COR between Day 1 and Day 3 oocytes. Increasing the size of granules in synthetic images recapitulated the age-associated changes in COR. Manual measurements validated that the cytoplasmic granules in oocytes become larger with aging. CONCLUSIONS: The Max-min value and COR objectively quantify age-related changes in C. elegans oocyte in Nomarski DIC microscopy images. Our methods provide new opportunities for understanding the mechanism underlying oocyte aging.

  39. jMorp updates in 2020: large enhancement of multi-omics data resources on the general Japanese population. International-journal

    Shu Tadaka, Eiji Hishinuma, Shohei Komaki, Ikuko N Motoike, Junko Kawashima, Daisuke Saigusa, Jin Inoue, Jun Takayama, Yasunobu Okamura, Yuichi Aoki, Matsuyuki Shirota, Akihito Otsuki, Fumiki Katsuoka, Atsushi Shimizu, Gen Tamiya, Seizo Koshiba, Makoto Sasaki, Masayuki Yamamoto, Kengo Kinoshita

    Nucleic acids research　49　(D1)　D536-D544　2021/01/08

    DOI： 10.1093/nar/gkaa1034 　

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    In the Tohoku Medical Megabank project, genome and omics analyses of participants in two cohort studies were performed. A part of the data is available at the Japanese Multi Omics Reference Panel (jMorp; https://jmorp.megabank.tohoku.ac.jp) as a web-based database, as reported in our previous manuscript published in Nucleic Acid Research in 2018. At that time, jMorp mainly consisted of metabolome data; however, now genome, methylome, and transcriptome data have been integrated in addition to the enhancement of the number of samples for the metabolome data. For genomic data, jMorp provides a Japanese reference sequence obtained using de novo assembly of sequences from three Japanese individuals and allele frequencies obtained using whole-genome sequencing of 8,380 Japanese individuals. In addition, the omics data include methylome and transcriptome data from ∼300 samples and distribution of concentrations of more than 755 metabolites obtained using high-throughput nuclear magnetic resonance and high-sensitivity mass spectrometry. In summary, jMorp now provides four different kinds of omics data (genome, methylome, transcriptome, and metabolome), with a user-friendly web interface. This will be a useful scientific data resource on the general population for the discovery of disease biomarkers and personalized disease prevention and early diagnosis.

  40. Texture-Based Screening to Identify Genes Involved in Reproductive Aging in Caenorhabditis Elegans

    Momoko Imakubo, Koji Kyoda, Hiroya Itoga, Jun Takayama, Shuichi Onami

    International Journal of Bioscience, Biochemistry and Bioinformatics　11　(3)　40-49　2021

    Publisher: International Academy Publishing (IAP)

    DOI： 10.17706/ijbbb.2021.11.3.40-49 　

    eISSN： 2010-3638

  41. Improvement and Evaluation of a Mathematical Model for Fertilization Calcium Waves in Caenorhabditis Elegans Peer-reviewed

    Imakubo Momoko, Takayama Jun, Onami Shuichi

    IPSJ Transactions on Bioinformatics　11　(0)　24-30　2018

    Publisher: Information Processing Society of Japan

    DOI： 10.2197/ipsjtbio.11.24 　

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    <p>Ca2+ waves propagate through the oocyte during fertilization, activate the oocyte and induce embryonic development. Ca2+-induced Ca2+-release (CICR) is a mechanism of Ca2+ wave formation. We previously quantified the Ca2+ waves in the nematode Caenorhabditis elegans by using high-speed imaging and image analysis. We found that the waves consist of a rapid local rise at the point of sperm entry and a slow global wave. We demonstrated that the Nagumo model, which models the CICR by a reaction-diffusion equation, can produce a similar biphasic waveform. However, the model cannot represent the observed gradual decrease in maximum Ca2+ concentration with increasing distance from the point of sperm entry. In this study, we introduced a linear monotonically decreasing function into the reaction part of the Nagumo model. We demonstrated that our new model can produce the gradual decrease in maximum Ca2+ concentration with increasing distance from the point of sperm entry and a biphasic waveform simultaneously.</p>

  42. In vivo live imaging of calcium waves and other cellular processes during fertilization in Caenorhabditis elegans Peer-reviewed

    Takayama J, Fujita M, Onami S

    Bio-protocol　7　(7)　2017/04

  43. AI創薬に向けた複雑な疾患の遺伝統計学モデル

    高山 順, 田宮 元

    日本化学会情報化学部会誌　35　(2)　158-158　2017

    Publisher: 公益社団法人 日本化学会・情報化学部会

    DOI： 10.11546/cicsj.35.158 　

    ISSN： 0913-3747

  44. The Sperm TRP-3 Channel Mediates the Onset of a Ca2+ Wave in the Fertilized C-elegans Oocyte Peer-reviewed

    Jun Takayama, Shuichi Onami

    CELL REPORTS　15　(3)　625-637　2016/04

    DOI： 10.1016/j.celrep.2016.03.040 　

    ISSN： 2211-1247

  45. Bootstrap Resampling Technique to Evaluate the Reliability of the Optimal Liposome Formulation: Skin Permeability and Stability Response Variables Peer-reviewed

    Sureewan Duangjit, Praneet Opanasopit, Theerasak Rojanarata, Jun Takayama, Kozo Takayama, Tanasait Ngawhirunpat

    BIOLOGICAL & PHARMACEUTICAL BULLETIN　37　(9)　1543-1549　2014/09

    DOI： 10.1248/bpb.b14-00361 　

    ISSN： 0918-6158

  46. Environmental Alkalinity Sensing Mediated by the Transmembrane Guanylyl Cyclase GCY-14 in C. elegans Peer-reviewed

    Takashi Murayama, Jun Takayama, Mayuki Fujiwara, Ichiro N. Maruyama

    CURRENT BIOLOGY　23　(11)　1007-1012　2013/06

    DOI： 10.1016/j.cub.2013.04.052 　

    ISSN： 0960-9822

  47. Improving spinning disk confocal microscopy by preventing pinhole cross-talk for intravital imaging (vol 110, pg 3399, 2013) Peer-reviewed

    Togo Shimozawa, Kazuo Yamagata, Takefumi Kondo, Shigeo Hayashi, Atsunori Shitamukai, Daijiro Konno, Fumio Matsuzaki, Jun Takayama, Shuichi Onami, Hiroshi Nakayama, Yasuhito Kosugi, Tomonobu M. Watanabe, Katsumasa Fujita, Yuko Mimori-Kiyosue

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　110　(15)　6240-6240　2013/04

    DOI： 10.1073/pnas.1303361110 　

    ISSN： 0027-8424

  48. Improving spinning disk confocal microscopy by preventing pinhole cross-talk for intravital imaging Peer-reviewed

    Togo Shimozawa, Kazuo Yamagata, Takefumi Kondo, Shigeo Hayashi, Atsunori Shitamukai, Daijiro Konno, Fumio Matsuzaki, Jun Takayama, Shuichi Onami, Hiroshi Nakayama, Yasuhito Kosugi, Tomonobu M. Watanabe, Katsumasa Fujita, Yuko Mimori-Kiyosue

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA　110　(9)　3399-3404　2013/02

    DOI： 10.1073/pnas.1216696110 　

    ISSN： 0027-8424

  49. Single-cell transcriptional analysis of taste sensory neuron pair in Caenorhabditis elegans Peer-reviewed

    Jun Takayama, Serge Faumont, Hirofumi Kunitomo, Shawn R. Lockery, Yuichi Iino

    NUCLEIC ACIDS RESEARCH　38　(1)　131-142　2010/01

    DOI： 10.1093/nar/gkp868 　

    ISSN： 0305-1048

    eISSN： 1362-4962

  50. Lateralized Gustatory Behavior of C. elegans Is Controlled by Specific Receptor-Type Guanylyl Cyclases Peer-reviewed

    Christopher O. Ortiz, Serge Faumont, Jun Takayama, Heidi K. Ahmed, Andrew D. Goldsmith, Roger Pocock, Kathryn E. McCormick, Hirofumi Kunimoto, Yuichi Iino, Shawn Lockery, Oliver Hobert

    CURRENT BIOLOGY　19　(12)　996-1004　2009/06

    DOI： 10.1016/j.cub.2009.05.043 　

    ISSN： 0960-9822

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Misc. 9

  1. Advancing genomic data analysis and AI technology in rare diseases

    鈴木智尚, 高山順, 田宮元, 高山順, 田宮元, 高山順, 田宮元

    実験医学　42　(1)　2024

    ISSN： 0288-5514

  2. 生命科学研究用の特化型シミュレータの開発および特化型シミュレータ群の構築

    勝間秀人, 勝間秀人, 高山順, 遠里由佳子, 京田耕司, 大浪修一, 大浪修一

    日本細胞生物学会大会(Web)　68th　ROMBUNNO.T3‐12 (WEB ONLY)　2016

  3. 線虫C.elegans RNAi胚の核分裂動態の定量計測と表現型解析

    遠里由佳子, 岡田初美, 高山順, 京田耕司, 大浪修一

    第15回産総研・産技連LS-BT合同研究発表会要旨集,2016　041　2016

  4. CRISPR‐Cas9法による線虫C.elegansの全胚性致死遺伝子へのGFP付加の効率評価

    古島理恵, 高山順, 京田耕司, 大浪修一

    日本分子生物学会年会プログラム・要旨集(Web)　39th　ROMBUNNO.1LBA‐097 (WEB ONLY)　2016

  5. 線虫C.elegans RNAi胚の核分裂動態の時空間定量計測と計算表現型解析

    遠里由佳子, 岡田初美, 高山順, 京田耕司, 大浪修一

    日本生化学会大会(Web)　88th　4T21L-02(3P0811) (WEB ONLY)　2015

  6. Alkaline pH sensation mediated by a Caenorhabditis elegans transmembrane guanylyl cyclase

    Takashi Murayama, Mayuki Fujiwara, Jun Takayama, Ichiro Maruyama

    NEUROSCIENCE RESEARCH　68　E386-E386　2010

    DOI： 10.1016/j.neures.2010.07.1708 　

    ISSN： 0168-0102

  7. Gene expression profiling of single chemosensory neurons of the nematode Caenorhabditis elegans

    Jun Takayama, Hirofumi Kunitomo, Yuichi Iino

    NEUROSCIENCE RESEARCH　61　S179-S179　2008

    ISSN： 0168-0102

  8. 単一神経細胞の遺伝子発現プロファイリングによる線虫ASE神経で左右非対称に発現する遺伝子の同定

    TAKAYAMA JUN, KUNITOMO HIROFUMI, IINO YUICHI

    生化学　4P-0721　2007

    ISSN： 0037-1017

  9. 線虫 C.elegans 感覚神経細胞の遺伝子発現プロファイリング

    TAKAYAMA JUN, KUNITOMO HIROFUMI, IINO YUICHI

    日本分子生物学会年会講演要旨集　28th　365　2005/11/25

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Presentations 23

  1. Population-specific reference genome and rapid WGS analyses for rare diseases Invited

    Jun Takayama

    Human Genetics Asia 2023（HGA2023）　2023/10/13

  2. カルテのテキストデータを用いたリアルワールドな医療知識グラフの構築

    仁宮 洸太, 高山 順, 田宮 元

    第5回日本メディカルAI学会学術集会　2023/06/18

  3. Tohoku Medical Megabank Project, an Integrated Biobank in Japan.

    Jun Takayama

    Population-scale Genomics Summit in Singapore　2022

  4. 日本人基準ゲノム配列とオントロジーベースのAIによる疾患ゲノム解析の高精度化

    髙山 順

    第56回 糖尿病学の進歩　2022

  5. 日本人基準ゲノムG1の構築と小児希少疾患の全エクソーム解析への応用

    高山 順

    第27回日本遺伝子診療学会大会　2020

  6. 日本人基準ゲノムJG1の構築 Invited

    高山 順

    日本人類遺伝学会第64回大会　2019

  7. Towrd an ethnic reference genome. Invited

    Jun Takayama

    HUGO Human Genome Meeting　2019

  8. A sperm-derived ion channel TRP-3 induces a Ca2+ wave in the fertilized C. elegans oocyte. International-presentation

    Takayama Jun, Shuichi Onami

    20th International C. elegans Meeting　2015/06/25

  9. Sperm-derived TRP-3 channel mediates the onset of the calcium wave in the fertilized egg of Caenorhabditis elegans International-presentation

    Takayama Jun, Shuichi Onami

    C. elegans Development, Cell Biology and Gene Expression Meeting in association with The 6th Asia-Pacific C. elegans Meeting　2014/07

  10. Sperm-derived TRP-3 channel mediates the onset of the fertilization calcium wave in C. elegans

    Takayama Jun, Shuichi Onami

    2014/05

  11. Sperm TRP-3 channel mediates the onset of the fertilization calcium wave in C. elegans

    Takayama Jun, Shuichi Onami

    2013/12/03

  12. Sperm-derived TRP-3 channel specifies the onset of the fertilization Ca2+ wave in the oocyte of C. elegans International-presentation

    Takayama Jun, Shuichi Onami

    19th International C. elegans Meeting　2013/06/27

  13. Timely generation of the biphasic calcium wave is ensured by the sperm TRP-3 channel in C. elegans fertilization.

    Takayama Jun, Shuichi Onami

    2012/12/13

  14. Sperm TRP-3 channel ensures the timely generation of the biphasic calcium wave in C. elegans fertilization. International-presentation

    Takayama Jun, Shuichi Onami

    The International Symposium on the Mechanisms of Sexual Reproduction in Animals and Plants　2012/11/14

  15. Timely generation of the fertilization calcium wave by a sperm TRP channel International-presentation

    Takayama Jun, Shuichi Onami

    C. elegans Development, Cell Biology & Gene Expression Meeting 2012　2012/06/08

  16. Biphasic traveling calcium wave during fertilization is generated independently of a sperm-supplied egg activation factor SPE-11 in Caenorhabditis elegans International-presentation

    Takayama Jun, Shuichi Onami

    51st American Society for Cell Biology Annual Meeting　2011/12/04

  17. Sperm-egg fusion generates a biphasic traveling calcium wave in Caenorhabditis elegans International-presentation

    Takayama Jun, Shuichi Onami

    18th International C. elegans Meeting　2011/06/24

  18. C. elegansの受精における二相性進行カルシウム波の発見

    高山 順, 大浪 修一

    第33回日本分子生物学会年会 第83回日本生化学会大会 合同大会　2010/12/10

  19. Identification of genes expressed left/right asymmetrically in ASE neurons of C. elegans. International-presentation

    Takayama Jun, Serge Faumont, Hirofumi Kunitomo, Shawn Lockery, Yuichi Iino

    Neuronal development, synaptic function & behavior C. elegans topic meeting #2　2008

  20. 単一神経細胞の遺伝子発現プロファイリングによる線虫ASE神経で左右非対称に発現する遺伝子の同定

    高山 順, 国友 博文, 飯野 雄一

    第30回日本分子生物学会年会 第80回日本生化学会大会 合同大会　2007/12/14

  21. Identification of genes expressed asymmetrically in the left/right ASE sensory neurons by the mRNA tagging method International-presentation

    Takayama Jun, Takeshi Adachi, Masahiro Tomioka, Hirofumi Kunitomo, Yuichi Iino

    16th International C. elegans Meeting　2007

  22. Gene expression profiling of amphid sensory neurons of the nematode C. elegans. International-presentation

    Takayama Jun, Hirofumi Kunitomo, Yuichi Iino

    2nd East Asia C. elegans Meeting　2006

  23. 線虫 C. elegans 感覚神経細胞の遺伝子発現プロファイリング

    高山 順, 国友 博文, 飯野 雄一

    第28回日本分子生物学会年会　2005/11/25

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Research Projects 4

  1. 深層学習による大規模ゲノムコホートの次世代シークエンス解析 Competitive

    高山 順

    Offer Organization: 文部科学省

    System: 基盤研究C

    2019/04 - 2022/03

  2. Elucidating the physiological significance of the fertilization calcium waves through the idenfication of novel channels Competitive

    Takayama Jun

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Young Scientists (B)

    Institution: Institute of Physical and Chemical Research

    2015 - 2017

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    Fertilization calcium waves are a conserved signal that triggers both animal and plant embryonic development. The calcium waves are thought to be propagated by the action of the IP3 receptor calcium channels. However, in the nematode C. elegans, involvement of a novel channel is suggested. In this study, we aimed to identify calcium channels that are responsible for the propagation of the calcium waves. We generated a transgenic C. elegans strain that expresses the genetically-encoded calcium indicator GCaMP6s in the germline. By using this transgenic strain, we conducted a feeding RNA interference screen. We identified several candidate genes that might be involved in the calcium wave propagation.

  3. Functional genomics of the chemosensory neurons of C.elegans

    KUNITOMO Hirofumi, IINO Yuichi, TAKAYAMA Jun

    Offer Organization: Japan Society for the Promotion of Science

    System: Grants-in-Aid for Scientific Research

    Category: Grant-in-Aid for Scientific Research (C)

    Institution: The University of Tokyo

    2007 - 2008

  4. 線虫C.elegans頭部感覚神経の遺伝子発現プロファイリング Competitive

    高山 順

    Offer Organization: 日本学術振興会

    System: 特別研究員奨励費(DC1)

    Category: 特別研究員奨励費

    Institution: 東京大学

    2006 - 2008

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    前年度までの研究により線虫の味覚神経ASEで左右非対称に発現する遺伝子の候補を得、本年度はこれらの神経の解析に集中した。候補の中から蛍光タンパク質レポーター実験により、ASER神経に強く発現する遺伝子を8個、ASEL神経に偏って発現する遺伝子を1個、新規に同定した。この中には、受容体型グアニル酸シクラーゼ、分泌性タンパク質、TRPCチャネル、機能未知の遺伝子が含まれていた。これまでASEL/Rで異なる発現パターンを示す遺伝子としてはグアニル酸シクラーゼと分泌性タンパク質のみが知られていたが、本研究によりASEL/Rが今まで考えられていたよりも多くの面で異なる可能性が示唆された。変異体を用いてこれらの遺伝子の発現制御を調べたところ、他の既知の遺伝子群と共通した制御を受けていることが明らかとなった。このことから、1つの共通した制御ネットワークがASEL/R分化のすべての側面を制御している可能性が強く示唆された。ASE神経で左右非対称に発現する遺伝子の機能解析を米国コロンビア大学のOliver Hobert博士らと共同で行った。ASEL細胞に偏って発現するgcy-14遺伝子の変異体およびトランスジェニック体を用いた実験から、GCY-14がASEL細胞における外界の金属イオンの受容に、細胞自律的に関わることを示した。また変異型gcy-14遺伝子を用いたレスキュー実験により、細胞外リガンド結合様ドメイン・細胞内シクラーゼドメインが必須であること、および他のGCYタンパク質と共同して機能する可能性が示唆された。本手法が細胞特異的な機能に関わる遺伝子を同定しうる有用な手法であることが示された。