ArticleAmerican journal of human genetics2021
Loss of C2orf69 defines a fatal autoinflammatory syndrome in humans and zebrafish that evokes a glycogen-storage-associated mitochondriopathy.
Erratum issuedOpen access · bronzeAbstract read
In one paragraph
Article in American journal of human genetics, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 9 papers, 1 of them a synthesis that pooled it.
0numbers the graph read from it
0cells of the map it votes in
9citing papers in PubMed, 1 pooled it
1.3field-weighted citation impact, top 20% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
9 citing papers in PubMed, 1 synthesis or guideline pooled it, 22 citations in OpenAlex.
- Smoking Status and Type 2 Diabetes, and Cardiovascular Disease: A Comprehensive Analysis of Shared Genetic Etiology and Causal Relationship.Frontiers in endocrinology · 2022Pooled it
- Decoding variants of uncertain significance in systemic autoinflammatory diseases.Nature reviews. Rheumatology · 2026Review
- A rare autoinflammatory syndrome associated with a C2orf69 frameshift mutation: a case report.Immunologic research · 2025Article
- Identification and validation of oxidative stress-related diagnostic markers for recurrent pregnancy loss: insights from machine learning and molecular analysis.Molecular diversity · 2025Article
- Review
- Zebrafish: A Relevant Genetic Model for Human Primary Immunodeficiency (PID) Disorders?International journal of molecular sciences · 2023Review
- Low aerobic capacity in McArdle disease: A role for mitochondrial network impairment?Molecular metabolism · 2022Article
- Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee.Journal of clinical immunology · 2022Article
- Common methods in mitochondrial research (Review).International journal of molecular medicine · 2022Article
Corrections and comments
- Erratum issued
Authors and funding
72 authors at 20 institutions in 11 countries.
Hui Hui WongInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
Sze Hwee SeetInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
Michael MaierLaboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
Ayse GurelDepartment of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
Ricardo Moreno TraspasLaboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
Cheryl LeeInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore 169857, Singapore.
Shan ZhangDepartment of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
Beril TalimPediatric Pathology Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
Abigail Y T LohInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
Crystal Y ChiaLaboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
Tze Shin TeohLaboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
Danielle SngLaboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
Jarred RensvoldDepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Morgridge Institute for Research, Madison, WI 53715, USA.
Sule UnalPediatric Hematology Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey; Research Center of Fanconi Anemia and Other Inherited Bone Marrow Failure Syndromes, Hacettepe University, Ankara 06230, Turkey.
Evgenia ShishkovaNational Center for Quantitative Biology of Complex Systems, Madison, WI 53562, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53562, USA.
Ece CepniInstitute of Health Sciences, Koç University, 34010 Istanbul, Turkey.
Fatima M NathanYale-NUS College, 12 College Avenue West, Singapore 138610, Singapore.
Fernanda L SirotaBioinformatics Institute, A(∗)STAR, Biopolis, Singapore 138671, Singapore.
Chao LiangDepartment of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
Nese YaraliAnkara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara 06110, Turkey.
Pelin O Simsek-KiperPediatric Genetics Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
Tadahiro MitaniDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Serdar CeylanerIntergen Genetic Diagnosis Center, Ankara 06680, Turkey.
Ozlem Arman-BilirAnkara Child Health and Diseases Hematology Oncology Training and Research Hospital, Ankara 06110, Turkey.
Hamdi MbarekQatar Genome Program, Qatar Foundation Research, Development and Innovation, Qatar Foundation, Doha, Qatar.
Fatma GumrukPediatric Hematology Unit, Department of Pediatrics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey; Research Center of Fanconi Anemia and Other Inherited Bone Marrow Failure Syndromes, Hacettepe University, Ankara 06230, Turkey.
Stephanie EfthymiouMolecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK.
Deniz Uğurlu Çi MenMedical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey.
Danai GeorgiadouLaboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
Kortessa SotiropoulouInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
Henry HouldenDepartment of Neuromuscular Diseases, UCL Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Franziska PaulInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
Davut PehlivanDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA.
Candice LainéParis University, Imagine Institute, Paris 75015, France; Laboratory of Human Genetics of Infectious Disease, Necker Branch, INSERM U1163, Paris, France.
Guoliang ChaiRady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
Nur Ain AliLaboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
Siew Chin ChooLaboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore.
Soh Sok KengInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore.
Bertrand BoissonParis University, Imagine Institute, Paris 75015, France; Laboratory of Human Genetics of Infectious Disease, Necker Branch, INSERM U1163, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA.
Elanur YılmazMedical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey.
Shifeng XueInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore.
Joshua J CoonMorgridge Institute for Research, Madison, WI 53715, USA; National Center for Quantitative Biology of Complex Systems, Madison, WI 53562, USA; Department of Biomolecular Chemistry, University of Wisconsin-Madison, Madison, WI 53562, USA; Department of Chemistry, University of Wisconsin-Madison, Madison, WI 53562, USA.
Thanh Thao Nguyen LyInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Department of Biological Sciences, National University of Singapore, Singapore 117558, Singapore.
Naser GilaniFarabi Medical Laboratory, Erbil, Iraq.
Dana HasbiniChief Division Pediatric Neurology, Department of Pediatrics, Rafic Hariri University Hospital, Beirut, Lebanon.
Hulya KayseriliMedical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey.
Maha S ZakiClinical Genetics Department, National Research Centre, Cairo 12622, Egypt.
Robert J IsfortCorporate Research, The Procter and Gamble Company, Cincinnati, OH 45040, USA.
Natalia OrdonezGenomic Research, CENTOGENE GmbH, 18055 Rostock, Germany.
Kornelia TripolszkiGenomic Research, CENTOGENE GmbH, 18055 Rostock, Germany.
Peter BauerGenomic Research, CENTOGENE GmbH, 18055 Rostock, Germany.
Nima RezaeiResearch Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran 14194, Iran; Network of Immunity in Infection, Malignancy and Autoimmunity, Universal Scientific Education and Research Network, Tehran 14197, Iran.
Simin SeyedpourLaboratoire d'analyses spécialisé en Génétique, Tunis 1082, Tunisia.
Ghamar Taj KhotaeiDepartment of Pediatric Infectious Diseases, Children's Medical Center, Tehran University of Medical Sciences, Tehran 14194, Iran.
Charles C BascomCorporate Research, The Procter and Gamble Company, Cincinnati, OH 45040, USA.
Reza MaroofianMolecular and Clinical Sciences Institute, St. George's University of London, Cranmer Terrace, London SW17 0RE, UK.
Myriam ChaabouniLaboratoire d'analyses spécialisé en Génétique, Tunis 1082, Tunisia.
Afaf AlsubhiDivision of Genetics, Department of Pediatrics, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, MNGHA, Riyadh 14611, Saudi Arabia; King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, MNGHA, Riyadh 11481, Saudi Arabia.
Wafaa EyaidDivision of Genetics, Department of Pediatrics, King Abdullah Specialized Children Hospital, King Abdulaziz Medical City, MNGHA, Riyadh 14611, Saudi Arabia; King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, MNGHA, Riyadh 11481, Saudi Arabia.
Sedat IşıkayDepartment of Pediatrics, Division of Neurology, University of Gaziantep, School of Medicine, Gaziantep 27310, Turkey.
Joseph G GleesonRady Children's Institute for Genomic Medicine, San Diego, CA 92123, USA; Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA.
James R LupskiDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
Jean-Laurent CasanovaParis University, Imagine Institute, Paris 75015, France; Laboratory of Human Genetics of Infectious Disease, Necker Branch, INSERM U1163, Paris, France; St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA; Pediatric Immunology-Hematology Unit, Assistance Publique-Hôpitaux de Paris, Necker Hospital for Sick Children, Paris 75015, France; Howard Hughes Medical Institute, New York, NY 10065, USA.
David J PagliariniDepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Morgridge Institute for Research, Madison, WI 53715, USA; National Center for Quantitative Biology of Complex Systems, Madison, WI 53562, USA; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA; Department of Biochemistry, University of Wisconsin-Madison, Madison, WI 53706, USA.
Nurten A AkarsuDepartment of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
Sebastian Maurer-StrohBioinformatics Institute, A(∗)STAR, Biopolis, Singapore 138671, Singapore.
Arda CetinkayaDepartment of Medical Genetics, Faculty of Medicine, Hacettepe University, Ankara 06230, Turkey.
Aida Bertoli-AvellaGenomic Research, CENTOGENE GmbH, 18055 Rostock, Germany.
Ajay S MathuruInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Yale-NUS College, 12 College Avenue West, Singapore 138610, Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117593, Singapore.
Lena HoInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Cardiovascular and Metabolic Diseases, Duke-NUS Medical School, Singapore 169857, Singapore.
Frederic A BardInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore. Electronic address: fbard@imcb.a-star.edu.sg.
Bruno ReversadeInstitute of Molecular and Cell Biology, A(∗)STAR, Biopolis, Singapore 138673, Singapore; Laboratory of Human Genetics & Therapeutics, Genome Institute of Singapore, A(∗)STAR, Biopolis, Singapore 138672, Singapore; Medical Genetics Department, Koç University School of Medicine, 34010 Istanbul, Turkey; Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore. Electronic address: bruno@reversade.com.
Agency for Science, Technology and Research · SGHacettepe University · TRCentogene (Germany) · DEKoç University · TRBaylor College of Medicine · USUniversity of Wisconsin–Madison · USChildren’s Institute · USInserm · FRKing Saud bin Abdulaziz University for Health Sciences · SAMinistry of Health · TRProcter & Gamble (United States) · USSt George's, University of London · GBChildren's Medical Center · IRGaziantep University · TRHoward Hughes Medical Institute · USIntergen (Turkey) · TRNational Hospital for Neurology and Neurosurgery · GBNational Research Centre · EGQatar Foundation · QARafik Hariri University Hospital · LB
Funding
Baylor-Johns Hopkins Center for Mendelian GeneticsU54HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2012 to 2015
$15.6MBaylor-Johns Hopkins Center for Mendelian GeneticsUM1HG006542 · NHGRI · JOHNS HOPKINS UNIVERSITY · PI VALLE, DAVID · 2016 to 2020
$14.5MTR&D 2 Metabolic Labels for Ultraplexed Protein Quantification p. 453P41GM108538 · NIGMS · UNIVERSITY OF WISCONSIN-MADISON · PI COON, JOSHUA J · 2016 to 2025
$13.1MSTRUCTURAL VARIATION IN NEUROLOGICAL DISEASER35NS105078 · NINDS · BAYLOR COLLEGE OF MEDICINE · PI LUPSKI, JAMES R. · 2018 to 2025
$6.0MSystems-to-structure approaches for defining mitochondrial protein functionR35GM131795 · NIGMS · WASHINGTON UNIVERSITY · PI David J Pagliarini · 2019 to 2026
$4.8MNHGRI NIH HHS U54 HG006542NHGRI NIH HHS UM1 HG006542NIGMS NIH HHS P41 GM108538NIGMS NIH HHS R35 GM131795NINDS NIH HHS R35 NS105078
Abstract
Human C2orf69 is an evolutionarily conserved gene whose function is unknown. Here, we report eight unrelated families from which 20 children presented with a fatal syndrome consisting of severe autoinflammation and progredient leukoencephalopathy with recurrent seizures; 12 of these subjects, whose DNA was available, segregated homozygous loss-of-function C2orf69 variants. C2ORF69 bears homology to esterase enzymes, and orthologs can be found in most eukaryotic genomes, including that of unicellular phytoplankton. We found that endogenous C2ORF69 (1) is loosely bound to mitochondria, (2) affects mitochondrial membrane potential and oxidative respiration in cultured neurons, and (3) controls the levels of the glycogen branching enzyme 1 (GBE1) consistent with a glycogen-storage-associated mitochondriopathy. We show that CRISPR-Cas9-mediated inactivation of zebrafish C2orf69 results in lethality by 8 months of age due to spontaneous epileptic seizures, which is preceded by persistent brain inflammation. Collectively, our results delineate an autoinflammatory Mendelian disorder of C2orf69 deficiency that disrupts the development/homeostasis of the immune and central nervous systems.
Indexed as
AnimalsBiological EvolutionCell LineCRISPR-Cas SystemsEncephalitisFemaleGenes, RecessiveGlycogenHumansInflammationMaleMembrane ProteinsMitochondrial DiseasesPedigreeSeizuresZebrafishGlycogenMembrane ProteinsC2ORF69, mitochondriopathy, inflammation, GBE1, encephalopathy, zebrafish, Elbracht-Işikay syndrome, lipase, glycogen, Mendelian genetics
Identifiers
What OpenQuestion holds
Textmetadata
Read underepoch 390
Registered trials
None linked
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.