Article
Genetics & Heredity
Fang Shen, Yongjia Yang, Yu Zheng, Pengcheng Li, Zhenqing Luo, Yuyan Fu, Guanghui Zhu, Haibo Mei, Shanlin Chen, Yimin Zhu
Summary: This study identified unique missense variants in MECOM gene associated with congenital radioulnar synostosis (RUS) in 8 families. These variants were mainly clustered within the ninth zinc finger motif of the EVI1 protein and were found to be related to finger malformations without hematological abnormalities. Functional experiments showed that specific MECOM variant led to alterations in TGF-beta-mediated transcriptional responses.
GENETICS IN MEDICINE
(2022)
Article
Genetics & Heredity
Elizabeth Wall, Joan Forsyth, Esther Kinning, Tamas Marton
Summary: We present a case of a fetus with hydrops, congenital heart disease, and bilateral radioulnar synostosis caused by a novel pathogenic MECOM variant. Whole genome sequencing identified a de novo heterozygous loss-of-function variant in MECOM, associated with Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia 2 (RUSAT-2). This case highlights the importance of detailed phenotyping with post-mortem examination and the use of broad sequencing approaches.
PRENATAL DIAGNOSIS
(2023)
Review
Hematology
Julia T. Warren, Jorge Di Paola
Summary: In this article, the genetic etiology of inherited thrombocytopenia syndromes and the validation of new genetic discoveries are discussed. Through international collaboration and research efforts, over 40 genes associated with thrombocytopenia have been identified.
Article
Hematology
Koki Nagai, Tetsuya Niihori, Akihiko Muto, Yoshikazu Hayashi, Taiki Abe, Kazuhiko Igarashi, Yoko Aoki
Summary: Radioulnar synostosis with amegakaryocytic thrombocytopenia (RUSAT) is an inherited bone marrow failure syndrome caused by missense mutations in the MECOM gene. Knockin mice harboring RUSAT-associated MECOM mutations recapitulate the bone marrow dysfunction observed in RUSAT patients.
Article
Genetics & Heredity
Michell M. Lozano M. Chinga, Alison A. A. Bertuch, Zeinab Afify, Kaylee Dollerschell, Joanne I. I. Hsu, Tami D. D. John, Emily S. S. Rao, Robert Grant Rowe, Vijay G. G. Sankaran, Akiko Shimamura, David A. A. Williams, Taizo A. A. Nakano
Summary: The MECOM gene is crucial for hematopoietic stem cell self-renewal and maintenance. Variants in this gene have been associated with various disorders, such as congenital thrombocytopenia, radioulnar synostosis, and bone marrow failure. The phenotypic spectrum of MECOM-associated syndromes continues to expand, and more pathogenic variants are being identified.
AMERICAN JOURNAL OF MEDICAL GENETICS PART A
(2023)
Review
Hematology
Carlo L. Balduini
Summary: The new techniques in genetic analysis have allowed for the identification of more inherited thrombocytopenias and the study of a large number of patients. Recent research has shifted the understanding of this condition, revealing that most patients only have mild bleeding tendencies, but certain mutations can predispose them to serious diseases. As a result, the treatment approach needs to take these changes into consideration and make use of available new therapies.
Article
Biochemistry & Molecular Biology
Laura Arribas-Carreira, Cristina Dallabona, Michael A. Swanson, Joseph Farris, Elsebet Ostergaard, Konstantinos Tsiakas, Maja Hempel, Cecile Aquaviva-Bourdain, Stefanos Koutsoukos, Nicholas Stence, Martina Magistrati, Elaine B. Spector, Kathryn Kronquist, Mette Christensen, Helena G. Karstensen, Rene G. Feichtinger, Melanie T. Achleitner, J. Lawrence Merritt, Belen Perez, Magdalena Ugarte, Stephanie Grunewald, Anthony R. Riela, Natalia Julve, Jean-Baptiste Arnoux, Kasturi Haldar, Claudia Donnini, Rene Santer, Allan M. Lund, Johannes A. Mayr, Pilar Rodriguez-Pombo, Johan L. K. Van Hove
Summary: The H-protein encoded by GCSH plays a crucial role in protein lipoylation and one-carbon metabolism. Pathogenic variants in GCSH can lead to a broad clinical spectrum ranging from neonatal fatal glycine encephalopathy to developmental delay and behavioral problems. Functional studies show that these variants have a hypomorphic effect on mitochondrial activities and glycine metabolism.
Article
Genetics & Heredity
Leman Damla Kotan, Gaetan Ternier, Aydilek Dagdeviren Cakir, Hamdi Cihan Emeksiz, Ihsan Turan, Gaspard Delpouve, Asli Derya Kardelen, Bahar Ozcabi, Emregul Isik, Eda Mengen, Esra Deniz P. Cakir, Aysegul Yuksel, Sebahat Yilmaz Agladioglu, Semine Ozdemir Dilek, Olcay Evliyaoglu, Feyza Darendeliler, Fatih Gurbuz, Gamze Akkus, Bilgin Yuksel, Paolo Giacobini, A. Kemal Topaloglu
Summary: The study revealed that SEMA3F signaling through PLXNA1-A3 is involved in guiding human GnRH neurons and olfactory/vomeronasal nerve fibers. Rare missense variants in SEMA3F and PLXNA3 were identified in 15 patients from 11 families, with most variants predicted to be deleterious by functional assays. The study suggests that insufficiency in Semaphorin-3F signaling contributes to the pathogenesis of IHH.
GENETICS IN MEDICINE
(2021)
Article
Hematology
Masahiro Irie, Tetsuya Niihori, Tomohiro Nakano, Tasuku Suzuki, Saori Katayama, Kunihiko Moriya, Hidetaka Niizuma, Nobu Suzuki, Yuka Saito-Nanjo, Masaei Onuma, Takeshi Rikiishi, Atsushi Sato, Mayumi Hangai, Mitsuteru Hiwatari, Junji Ikeda, Reo Tanoshima, Norio Shiba, Yuki Yuza, Nobuyuki Yamamoto, Yoshiko Hashii, Motohiro Kato, Junko Takita, Miho Maeda, Yoko Aoki, Masue Imaizumi, Yoji Sasahara
Summary: This study retrospectively assessed the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) in infants with MECOM-associated syndrome. The results showed that HSCT with reduced-intensity conditioning (RIC) was effective and feasible, with all patients achieving stable engraftment and complete chimerization. There were no severe regimen-related toxicities, and only mild acute graft-versus-host disease was observed. Therefore, allogeneic HSCT with RIC is a promising treatment option for infants with MECOM-associated syndrome.
INTERNATIONAL JOURNAL OF HEMATOLOGY
(2023)
Article
Hematology
Oded Gilad, Orly Dgany, Sharon Noy-Lotan, Tanya Krasnov, Joanne Yacobovich, Ron Rabinowicz, Tracie Goldberg, Amir A. Kuperman, Abed Abu-Quider, Hagit Miskin, Noa Kapelushnik, Noa Mandel-Shorer, Shai Shimony, Dan Harlev, Tal Ben-Ami, Etai Adam, Carina Levin, Shraga Aviner, Ronit Elhasid, Sivan Berger-Achituv, Lilach Chaitman-Yerushalmi, Yona Kodman, Nino Oniashvilli, Michal Hameiri-Grosman, Shai Izraeli, Hannah Tamary, Orna Steinberg-Shemer
Summary: Prolonged cytopenias can be caused by various diseases, including leukemia predisposition. Accurate diagnosis of children with persistent cytopenias is crucial for appropriate treatment and prevention of leukemia.
Article
Hematology
Manuela Germeshausen, Matthias Ballmaier
Summary: CAMT is a rare inherited bone marrow failure syndrome characterized by mutations in the MPL gene. The disease has complex etiologies, with associations with radio-ulnar synostosis and the possibility of misdiagnosis with other IBMFS.
BEST PRACTICE & RESEARCH CLINICAL HAEMATOLOGY
(2021)
Article
Pediatrics
Yinying Zhang
Summary: This article presents a case of congenital bone marrow failure that was successfully treated with haploidentical bone marrow transplantation (BMT) and identifies a novel, de novo pathogenic variant in the MECOM gene.
TURKISH JOURNAL OF PEDIATRICS
(2022)
Article
Medicine, Research & Experimental
Camille A. Dash, Jill A. Madden, Christy Cummings, Melissa Rose, Sheria D. Wilson, Mari Mori, Pankaj B. Agrawal, Bimal P. Chaudhari, Monica H. Wojcik
Summary: Variants in MECOM gene can cause a rare bone marrow failure syndrome known as RUSAT2, which is associated with amegakaryocytic thrombocytopenia and radioulnar synostosis. Two preterm infants were reported to have severe symptoms of bone marrow failure at birth, including anemia, hydrops, and hemorrhages; however, no radioulnar synostosis was observed in either case, and both infants did not survive. Genomic sequencing revealed de novo variants in MECOM, supporting MECOM as a cause for bone marrow failure in utero and highlighting the importance of postmortem genomic investigation.
COLD SPRING HARBOR MOLECULAR CASE STUDIES
(2023)
Article
Genetics & Heredity
Rumiko Izumi, Toshiaki Takahashi, Naoki Suzuki, Tetsuya Niihori, Hiroya Ono, Naoko Nakamura, Shinichi Katada, Masaaki Kato, Hitoshi Warita, Maki Tateyama, Yoko Aoki, Masashi Aoki
Article
Clinical Neurology
Miyako Mizukami, Aki Ishikawa, Sachiko Miyazaki, Akiko Tsuzuki, Sakae Saito, Tetsuya Niihori, Akihiro Sakurai
Summary: This study presented a case of a 9-year-old female with a de novo missense variant in the CHD3 gene identified by whole exome sequencing. The case exhibited intellectual disability, speech impairment, autism, joint laxity, and dysmorphisms. The analysis suggests that CHD3 analysis is helpful for the diagnosis of neurodevelopmental disorders.
BRAIN & DEVELOPMENT
(2021)
Article
Genetics & Heredity
Aya Inoue-Shibui, Tetsuya Niihori, Michio Kobayashi, Naoki Suzuki, Rumiko Izumi, Hitoshi Warita, Kenju Hara, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Ichizo Nishino, Masashi Aoki, Yoko Aoki
Summary: A novel frameshift variant in the HSPB8 gene was identified in a large Japanese family with RVM, leading to severe respiratory failure and muscle atrophy in the paraspinal muscles. The frameshift mutation results in a predicted ILV sequence, which is associated with protein aggregation and may play a role in the pathogenesis of HSPB8-related RVM.
JOURNAL OF HUMAN GENETICS
(2021)
Article
Genetics & Heredity
Koki Nagai, Tetsuya Niihori, Nobuhiko Okamoto, Akane Kondo, Kenichi Suga, Tomoko Ohhira, Yasunobu Hayabuchi, Yukako Homma, Ryuji Nakagawa, Toshinobu Ifuku, Taiki Abe, Takeshi Mizuguchi, Naomichi Matsumoto, Yoko Aoki
Summary: Costello syndrome is an autosomal dominant disorder characterized by distinctive facial features, hypertrophic cardiomyopathy, skeletal abnormalities, intellectual disability, and predisposition to cancers, with germline variants in HRAS being identified in patients. In this study, it was found that small in-frame duplications within the HRAS gene enhance the activation of the ERK pathway, resulting in developmental abnormalities in zebrafish embryos or patients with Costello syndrome.
Article
Genetics & Heredity
Miyako Kanno, Mitsuyoshi Suzuki, Ken Tanikawa, Chikahiko Numakura, Shu-ichi Matsuzawa, Tetsuya Niihori, Yoko Aoki, Yoichi Matsubara, Satoshi Makino, Gen Tamiya, Satoshi Nakano, Ryo Funayama, Matsuyuki Shirota, Keiko Nakayama, Tetsuo Mitsui, Kiyoshi Hayasaka
Summary: PILBD is a heterogeneous disorder classified into syndromic and non-syndromic categories. In a family with dominantly inherited PILBD, a pathogenic variant CACYBP/SIP p.E177Q was found, leading to enhanced degradation of beta-catenin and delayed intrahepatic bile duct maturation. This discovery suggests that accurate regulation of beta-catenin concentration is crucial for bile duct development.
JOURNAL OF HUMAN GENETICS
(2022)
Article
Genetics & Heredity
Shin Ito, Aya Hashimoto, Kazunori Yamaguchi, Sadafumi Kawamura, Shingo Myoen, Maki Ogawa, Ikuro Sato, Takamichi Minato, Shingo Miyabe, Akira Nakazato, Keitaro Fujii, Mai Mochizuki, Haruna Fujimori, Keiichi Tamai, Tetsuya Niihori, Yoko Aoki, Akira Sugawara, Hironobu Sasano, Hiroshi Shima, Jun Yasuda
Summary: Carney complex (CNC) is a rare hereditary syndrome that involves endocrine dysfunction and the development of various types of tumors. This study reports a mother and son with CNC caused by an 8.57-kb deletion in the PRKAR1A gene. This novel deletion will facilitate molecular diagnosis of CNC.
MOLECULAR GENETICS & GENOMIC MEDICINE
(2022)
Letter
Hematology
Tetsuya Niihori, Reo Tanoshima, Yoji Sasahara, Atsushi Sato, Masahiro Irie, Yuka Saito-Nanjo, Ryo Funayama, Matsuyuki Shirota, Taiki Abe, Yuko Okuyama, Naoto Ishii, Keiko Nakayama, Shigeo Kure, Masue Imaizumi, Yoko Aoki
Article
Genetics & Heredity
Tomohiro Nakano, Yoji Sasahara, Atsuo Kikuchi, Kunihiko Moriya, Hidetaka Niizuma, Tetsuya Niihori, Matsuyuki Shirota, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Shigeo Kure
Summary: This study reveals the impact of POLE mutations on DNA replication and cell cycle progression, with mutant patients being highly susceptible to proteasome-dependent degradation in the nucleus, resulting in impaired DNA replication and cell cycle progression.
JOURNAL OF MEDICAL GENETICS
(2022)
Article
Genetics & Heredity
Yu Aihara, Matsuyuki Shirota, Atsuo Kikuchi, Yu Katata, Yu Abe, Tetsuya Niihori, Ryo Funayama, Keiko Nakayama, Yoko Aoki, Shigeo Kure
Summary: This case report describes a two-year-old girl with developmental delay, tremor, and ataxic gait, but no obvious dystonia. Exome sequencing identified a novel variant in the ANO3 gene, which has been associated with intellectual disability. The study suggests that specific variants in the transmembrane 4 domain of ANO3 may be a cause of childhood-onset movement disorder with intellectual disability, even in the absence of dystonia.
JOURNAL OF HUMAN GENETICS
(2023)
Article
Oncology
Hidekazu Shirota, Keigo Komine, Masanobu Takahashi, Shin Takahashi, Eisaku Miyauchi, Hidetaka Niizuma, Hiroshi Tada, Muneaki Shimada, Tetsuya Niihori, Yoko Aoki, Ikuko Sugiyama, Maako Kawamura, Jun Yasuda, Shuhei Suzuki, Takeshi Iwaya, Motonobu Saito, Tsuyoshi Saito, Hiroyuki Shibata, Toru Furukawa, Chikashi Ishioka
Summary: There has been a paradigm shift in cancer chemotherapy towards personalized medicine with molecular-targeted drugs. The Molecular Tumor Board (MTB) serves as a platform that integrates clinical and molecular features for clinical decisions. This study retrospectively analyzed cases discussed at the MTB, summarizing genetic alterations and treatment recommendations. The results provide valuable insights for simplifying treatment recommendations and improving personalized medicine accuracy.
Article
Pathology
Hirofumi Watanabe, Fumiyoshi Fujishima, Toru Motoi, Yayoi Aoyama, Tetsuya Niihori, Masanobu Takahashi, Sho Umegaki, Hisashi Oishi, Hiroshi Tada, Ryo Ichinohasama, Hironobu Sasano
Summary: Germline TP53 mutations are commonly found in LFS patients, leading to a predisposition to various cancers. This case study presents a unique liposarcoma in a patient with LFS, showing a novel c-myc amplification. The presence of c-myc amplification may indicate an LFS-related tumor, further expanding the understanding of MPLPS and LFS-related liposarcomas.
DIAGNOSTIC PATHOLOGY
(2022)
Article
Hematology
Masahiro Irie, Tetsuya Niihori, Tomohiro Nakano, Tasuku Suzuki, Saori Katayama, Kunihiko Moriya, Hidetaka Niizuma, Nobu Suzuki, Yuka Saito-Nanjo, Masaei Onuma, Takeshi Rikiishi, Atsushi Sato, Mayumi Hangai, Mitsuteru Hiwatari, Junji Ikeda, Reo Tanoshima, Norio Shiba, Yuki Yuza, Nobuyuki Yamamoto, Yoshiko Hashii, Motohiro Kato, Junko Takita, Miho Maeda, Yoko Aoki, Masue Imaizumi, Yoji Sasahara
Summary: This study retrospectively assessed the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) in infants with MECOM-associated syndrome. The results showed that HSCT with reduced-intensity conditioning (RIC) was effective and feasible, with all patients achieving stable engraftment and complete chimerization. There were no severe regimen-related toxicities, and only mild acute graft-versus-host disease was observed. Therefore, allogeneic HSCT with RIC is a promising treatment option for infants with MECOM-associated syndrome.
INTERNATIONAL JOURNAL OF HEMATOLOGY
(2023)
Article
Genetics & Heredity
Maako Kawamura, Hidekazu Shirota, Tetsuya Niihori, Keigo Komine, Masanobu Takahashi, Shin Takahashi, Eisaku Miyauchi, Hidetaka Niizuma, Atsuo Kikuchi, Hiroshi Tada, Muneaki Shimada, Naoki Kawamorita, Masayuki Kanamori, Ikuko Sugiyama, Mari Tsubata, Hitotshi Ichikawa, Jun Yasuda, Toru Furukawa, Yoko Aoki, Chikashi Ishioka
Summary: Cancer treatment is shifting towards personalized medicine, using genetic sequencing to identify therapeutic targets. This study retrospectively analyzed comprehensive genomic profiling (CGP) tests conducted at a hospital, focusing on the identification of presumed germline pathogenic variants (PGPV). The study found that confirmatory testing was recommended for 64 patients, with 17 patients testing positive for pathogenic variants. The results provide valuable insights for the management of secondary findings in genomic analysis.
JOURNAL OF HUMAN GENETICS
(2023)
Meeting Abstract
Oncology
Akifumi Nozawa, Yoko Aoki, Taiki Abe, Tetsuya Niihori, Michio Ozeki, Shiho Yasue, Saori Endo, Hidenori Ohnishi
PEDIATRIC BLOOD & CANCER
(2021)
Article
Cardiac & Cardiovascular Systems
Hideaki Suzuki, Yoshiaki Morita, Ryoko Saito, Shunsuke Tatebe, Tetsuya Niihori, Yoshikatsu Saiki, Satoshi Yasuda, Hiroaki Shimokawa
Summary: Danon disease, a genetic disorder, is characterized by autophagic vacuoles in muscles. The study found that Danon patients had high native T1 values in areas without LGE, supporting the differential diagnosis of this disease from other cardiomyopathies.
EUROPEAN HEART JOURNAL-CASE REPORTS
(2021)