Gene identification of rare genetic diseases by Multi-Omics analysis

2021 Fiscal Year Annual Research Report

• Project/Area Number: 19H03621
• Research Institution: National Center for Global Health and Medicine
• Principal Investigator: 三宅 紀子 国立研究開発法人国立国際医療研究センター, 研究所, 疾患ゲノム研究部 部長 (40523494)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: 単一遺伝子疾患 / 網羅的ゲノム解析 / 新規疾患遺伝子 / Multi-Omics

Outline of Annual Research Achievements

知的障害を合併する痙性対麻痺の兄弟例の全エクソーム解析により、ABHD16A遺伝子のホモ接合性ナンセンス変異を同定した。同定した当時は、まだ疾患遺伝子としての報告がなく、GeneMatcherという遺伝子と遺伝形式をマッチングサイトで他の症例を収集しようとしていたところ、他の研究グループから新規の痙性対麻痺の疾患遺伝子としての報告がなされた。我々の症例の変異は新規の変異であったが、臨床症状は報告例と同じように小児期発症、発達遅延、知的障害、言語障害、錐体外路障害、精神症状、脳画像異常所見（薄い脳梁、T2 MRIで高信号を認める）を呈しており、新しいタイプの痙性対麻痺であることが確立されtた。一方、我々の兄弟では特徴的な顔貌、睡眠障害、結節状の低色素性病変を呈していたが、他の症例では認められなかったことから、本症候群の合併症であるかどうかは今後の症例の集積で明らかにされるであろう（Miyake et al., 2021 Clin Genet）。
先天性クリコシド異常症のうち、COG1変異による報告は世界で5症例しか報告されていなかった。我々の解析により、新規のCOG1変異を持つ１症例が同定された。変異例が5例報告されているが、臨床情報が報告されているのが３例であったため、今回の自験例をまとめてCOG1変異による先天性クリコシド異常症の臨床像をまとめたところ、成長障害、発達遅延、特徴的な顔貌（小頭症、眼裂斜下、薄い口唇等）、短頸、脳・心臓・腎臓・骨格系の様々な異常を伴うことが分かった (Miyake et al., 2021 Clin Genet)。これら以外にも共同研究により新規疾患遺伝子ARF3を同定した。

Research Progress Status

令和3年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和3年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Victorian Clinical Genetics Services/Murdoch Children's Research Institute/The University of Melbourne(オーストラリア)
  • Country Name: AUSTRALIA
  • Counterpart Institution: Victorian Clinical Genetics Services/Murdoch Children's Research Institute/The University of Melbourne
• [Int'l Joint Research] University of Oxford/John Radcliffe Hospital(英国)
  • Country Name: UNITED KINGDOM
  • Counterpart Institution: University of Oxford/John Radcliffe Hospital
• [Int'l Joint Research] Hospital de Puerto Montt/Universidad de Chile(チリ)
  • Country Name: CHILE
  • Counterpart Institution: Hospital de Puerto Montt/Universidad de Chile
• [Int'l Joint Research] entre Hospitalier Saint-Louis/Hopital Armand Trousseau/CHU de Nantes(フランス)
  • Country Name: FRANCE
  • Counterpart Institution: entre Hospitalier Saint-Louis/Hopital Armand Trousseau/CHU de Nantes
• [Int'l Joint Research] University of Illinois at Chicago/Carolinas Medical Center/MIT(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: University of Illinois at Chicago/Carolinas Medical Center/MIT
• [Int'l Joint Research]
  • # of Other Countries: 5
• [Journal Article] Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome (2022)
  • Author(s): Miyatake S, Yoshida K, Koshimizu E, others, Miyake N, Shimohata T, Tanaka F, Mizuguchi T, Matsumoto N.
  • Journal Title: Brain Volume: 145 Pages: 1139～1150
  • DOI: 10.1093/brain/awab363
  • Peer Reviewed
• [Journal Article] Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants. (2022)
  • Author(s): Hamanaka K, Miyake N, Mizuguchi T, Miyatake S, Uchiyama Y, Tsuchida N, Sekiguchi F, Mitsuhashi S, Tsurusaki Y, Nakashima M, Saitsu H, Yamada K, Sakamoto M, Fukuda H, Ohori S, Saida K, Itai T, Azuma Y, Koshimizu E, Fujita A, Erturk B, Hiraki Y, Ch'ng GS, Kato M, Okamoto N, Takata A, Matsumoto N.
  • Journal Title: Genome Med Volume: 14 Pages: 40
  • DOI: 10.1186/s13073-022-01042-w
  • Peer Reviewed
• [Journal Article] Polymicrogyria in a child with KCNMA1-related channelopathy (2022)
  • Author(s): Graber D, Imagawa E, Miyake N, Matsumoto N, Miyatake S, Graber M, Isidor B.
  • Journal Title: Brain and Development Volume: 44 Pages: 173～177
  • DOI: 10.1016/j.braindev.2021.09.009
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Recurrent de novo missense variants in GNB2 can cause syndromic intellectual disability (2021)
  • Author(s): Tan NB, Pagnamenta AT, others, Matsumoto N, Miyake N, Sheffer R, Mor-Shaked H, Barnett CP, Byrne AB, Scott HS, Kraus A, Cappuccio G, Brunetti-Pierri N, Iorio R, Di Dato F, Pais LS, Yeung A, Tan TY, Taylor JC, Christodoulou J, White SM.
  • Journal Title: Journal of Medical Genetics Volume: 59 Pages: 511～516
  • DOI: 10.1136/jmedgenet-2020-107462
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A homozygous ABHD16A variant causes a complex hereditary spastic paraplegia with developmental delay, absent speech, and characteristic face (2021)
  • Author(s): Miyake N, Silva S, Troncoso M, Okamoto N, Andachi Y, Kato M, Iwabuchi C, Hirose M, Fujita A, Uchiyama Y, Matsumoto N.
  • Journal Title: Clinical Genetics Volume: 101 Pages: 359～363
  • DOI: 10.1111/cge.14097
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] SLC4A2 Deficiency Causes a New Type of Osteopetrosis (2021)
  • Author(s): Xue JY, Grigelioniene G, Wang Z, Nishimura G, Iida A, Matsumoto N, Tham E, Miyake N, Ikegawa S, Guo L.
  • Journal Title: Journal of Bone and Mineral Research Volume: 37 Pages: 226～235
  • DOI: 10.1002/jbmr.4462
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expanding the phenotypic spectrum of cardiospondylocarpofacial syndrome: From a detailed clinical and radiological observation of a boy with a novel missense variant in MAP3K7 (2021)
  • Author(s): Minatogawa M, Miyake N, Tsukahara Y, Tanabe Y, Uchiyama T, Matsumoto N, Kosho T.
  • Journal Title: American Journal of Medical Genetics Part A Volume: 188 Pages: 350～356
  • DOI: 10.1002/ajmg.a.62516
  • Peer Reviewed
• [Journal Article] De novo ARF3 variants cause neurodevelopmental disorder with brain abnormality (2021)
  • Author(s): Sakamoto M, Sasaki K, Sugie A, Nitta Y, Kimura T, Gursoy S, Cinleti T, Iai M, Sengoku T, Ogata K, Suzuki A, Okamoto N, Iwama K, Tsuchida N, Uchiyama Y, Koshimizu E, Fujita A, Hamanaka K, Miyatake S, Mizuguchi T, Taguri M, Ito S, Takahashi H, Miyake N, Matsumoto N.
  • Journal Title: Human Molecular Genetics Volume: 31 Pages: 69～81
  • DOI: 10.1093/hmg/ddab224
  • Peer Reviewed
• [Journal Article] Valine metabolites analysis in ECHS1 deficiency (2021)
  • Author(s): Kuwajima M, Kojima K, Osaka H, Hamada Y, Jimbo E, Watanabe M, Aoki S, Sato-Shirai I, Ichimoto K, Fushimi T, Murayama K, Ohtake A, Kohda M, Kishita Y, Yatsuka Y, Uchino S, Mimaki M, Miyake N, Matsumoto N, Okazaki Y, Ogata T, Yamagata T, Muramatsu K.
  • Journal Title: Molecular Genetics and Metabolism Reports Volume: 29 Pages: 100809～100809
  • DOI: 10.1016/j.ymgmr.2021.100809
  • Peer Reviewed / Open Access
• [Journal Article] Pathogenic variants in the survival of motor neurons complex gene GEMIN5 cause cerebellar atrophy (2021)
  • Author(s): Saida K, Tamaoki J, Sasaki M, Haniffa M, Koshimizu E, Sengoku T, Maeda H, Kikuchi M, Yokoyama H, Sakamoto M, Iwama K, Sekiguchi F, Hamanaka K, Fujita A, Mizuguchi T, Ogata K, Miyake N, Miyatake S, Kobayashi M, Matsumoto N.
  • Journal Title: Clinical Genetics Volume: 100 Pages: 722～730
  • DOI: 10.1111/cge.14066
  • Peer Reviewed
• [Journal Article] Comprehensive Genetic Analysis of Non-syndromic Autism Spectrum Disorder in Clinical Settings (2021)
  • Author(s): Ohashi K, Fukuhara S, Miyachi T, Asai T, Imaeda M, Goto M, Kurokawa Y, Anzai T, Tsurusaki Y, Miyake N, Matsumoto N, Yamagata T, Saitoh S.
  • Journal Title: Journal of Autism and Developmental Disorders Volume: 51 Pages: 4655～4662
  • DOI: 10.1007/s10803-021-04910-3
  • Peer Reviewed
• [Journal Article] Novel variants in aromatic L-amino acid decarboxylase deficiency: Case report of sisters with mild phenotype (2021)
  • Author(s): Hasegawa Y, Nishi E, Mishima Y, Sakaguchi T, Sekiguchi F, Miyake N, Kojima K, Osaka H, Matsumoto N, Okamoto N.
  • Journal Title: Brain and Development Volume: 43 Pages: 1023～1028
  • DOI: 10.1016/j.braindev.2021.07.002
  • Peer Reviewed
• [Journal Article] De novo pathogenic DHX30 variants in two cases (2021)
  • Author(s): Miyake N, Kim CA, Haginoya K, Castro MAA, Honjo RS, Matsumoto N.
  • Journal Title: Clinical Genetics Volume: 100 Pages: 350～351
  • DOI: 10.1111/cge.14013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] COG1‐congenital disorders of glycosylation: Milder presentation and review (2021)
  • Author(s): Salazar M, Miyake N, Silva S, Solar B, Papazoglu GM, Asteggiano CG, Matsumoto N
  • Journal Title: Clinical Genetics Volume: 100 Pages: 318～323
  • DOI: 10.1111/cge.13980
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Remitting and exacerbating white matter lesions in leukoencephalopathy with thalamus and brainstem involvement and high lactate (2021)
  • Author(s): Sawada D, Naito S, Aoyama H, Shiohama T, Ichikawa T, Imagawa E, Miyake N, Matsumoto N, Fujii K.
  • Journal Title: Brain and Development Volume: 43 Pages: 798～803
  • DOI: 10.1016/j.braindev.2021.03.008
  • Peer Reviewed
• [Journal Article] Clinical course of epilepsy and white matter abnormality linked to a novel DYRK1A variant (2021)
  • Author(s): Okazaki T, Yamada H, Matsuura K, Kasagi N, Miyake N, Matsumoto N, Adachi K, Nanba E, Maegaki Y.
  • Journal Title: Human Genome Variation Volume: 8 Pages: 26
  • DOI: 10.1038/s41439-021-00157-7
  • Peer Reviewed
• [Journal Article] Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2 (2021)
  • Author(s): Faundes V, Goh S, Akilapa R, Bezuidenhout H, others, Miyake N, Benoit V, Lederer D, Banka S.
  • Journal Title: Genetics in Medicine Volume: 23 Pages: 1202～1210
  • DOI: 10.1038/s41436-021-01119-8
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expanding the phenotypic spectrum of TNFRSF11A-associated dysosteosclerosis: a case with intracranial extramedullary hematopoiesis (2021)
  • Author(s): Xue JY, Simsek-Kiper PO, Utine GE, Yan L, Wang Z, Taskiran EZ, Karaosmanoglu B, Imren G, Gocmen R, Nishimura G, Matsumoto N, Miyake N, Ikegawa S, Guo L.
  • Journal Title: Journal of Human Genetics Volume: 66 Pages: 607～611
  • DOI: 10.1038/s10038-020-00891-w
  • Peer Reviewed
• [Journal Article] Complete sequencing of expanded SAMD12 repeats by long-read sequencing and Cas9-mediated enrichment (2021)
  • Author(s): Mizuguchi T, Toyota T, Miyatake S, Mitsuhashi S, Doi H, Kudo Y, Kishida H, Hayashi N, Tsuburaya RS, Kinoshita M, Fukuyama T, Fukuda H, Koshimizu E, Tsuchida N, Uchiyama Y, Fujita A, Takata A, Miyake N, Kato M, Tanaka F, Adachi H, Matsumoto N.
  • Journal Title: Brain Volume: 144 Pages: 1103～1117
  • DOI: 10.1093/brain/awab021
  • Peer Reviewed
• [Journal Article] A Brazilian case arising from a homozygous canonical splice site SLC35A3 variant leading to an in‐frame deletion (2021)
  • Author(s): Miyake N, de Oliveira Stephan B, Kim CA, Matsumoto N.
  • Journal Title: Clinical Genetics Volume: 99 Pages: 607～608
  • DOI: 10.1111/cge.13909
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel EXOSC9 variants cause pontocerebellar hypoplasia type 1D with spinal motor neuronopathy and cerebellar atrophy (2021)
  • Author(s): Sakamoto M, Iwama K, Sekiguchi F, Mashimo H, Kumada S, Ishigaki K, Okamoto N, Behnam M, Ghadami M, Koshimizu E, Miyatake S, Mitsuhashi S, Mizuguchi T, Takata A, Saitsu H, Miyake N, Matsumoto N.
  • Journal Title: Journal of Human Genetics Volume: 66 Pages: 401～407
  • DOI: 10.1038/s10038-020-00853-2
  • Peer Reviewed
• [Journal Article] The identification of two pathogenic variants in a family with mild and severe forms of developmental delay (2021)
  • Author(s): Miyake N, Heydari S, Garshasbi M, Saitoh S, Nasiri J, Hamanaka K, Takata A, Matsumoto N, Beheshti FH, Chaleshtori ARS.
  • Journal Title: Journal of Human Genetics Volume: 66 Pages: 445～448
  • DOI: 10.1038/s10038-020-0809-8
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Gain-of-Function MN1 Truncation Variants Cause a Recognizable Syndrome with Craniofacial and Brain Abnormalities (2021)
  • Author(s): Noriko Miyake
  • Organizer: American Society of Human Genetics
  • Int'l Joint Research / Invited
• [Presentation] 転写活性化因子MN1の機能獲得型変異によるヒト疾患の病態解明 (2021)
  • Author(s): 三宅紀子
  • Organizer: 第44回日本分子生物学会
  • Invited
• [Book] Progress in Heritable Soft Connective Tissue Diseases (2021)
  • Author(s): Miyake N, Kosho T, Matsumoto N
  • Total Pages: 15
  • Publisher: Springer