ArticleBrain : a journal of neurology2020
MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.
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Article in Brain : a journal of neurology, 2020. 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 28 papers.
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28 citing papers in PubMed.
- Iterative genetic testing identifiesJournal of human immunity · 2026Article
- Genetic Insights in Hindbrain Abnormalities Through Network Analysis Expose Key Biological Pathways in Hindbrain Development.Cerebellum (London, England) · 2025Article
- Extremely rare case report of CEBALID syndrome presenting as congenital arthrogryposis.BMC pediatrics · 2025Article
- Evolution of the essential geneProceedings of the National Academy of Sciences of the United States of America · 2025Article
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- Artificial intelligence-driven genotype-epigenotype-phenotype approaches to resolve challenges in syndrome diagnostics.EBioMedicine · 2025Article
- A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.Nature communications · 2024Article
- Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families.BMC medical genomics · 2024Article
- Systematic analysis of variants escaping nonsense-mediated decay uncovers candidate Mendelian diseases.American journal of human genetics · 2024Article
- A cell type-aware framework for nominating non-coding variants in Mendelian regulatory disorders.medRxiv : the preprint server for health sciences · 2023Article
- A Novel Pathogenic Variant in theJournal of pediatric genetics · 2023Article
- Combining globally search for a regular expression and print matching lines with bibliographic monitoring of genomic database improves diagnosis.Frontiers in genetics · 2023Article
- BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming.Stem cell reports · 2022Article
- Diagnosis and treatment of MN1 C-terminal truncation syndrome.Molecular genetics & genomic medicine · 2022Article
- DNA methylation landscapes from pig's limbic structures underline regulatory mechanisms relevant for brain plasticity.Scientific reports · 2022Article
- Human Cerebellar Development and Transcriptomics: Implications for Neurodevelopmental Disorders.Annual review of neuroscience · 2022Review
- Underlying genetic etiologies of congenital diaphragmatic hernia.Prenatal diagnosis · 2022Review
- Identification of novel SSX1 fusions in synovial sarcoma.Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc · 2022Article
- Recurrence- and Malignant Progression-Associated Biomarkers in Low-Grade Gliomas and Their Roles in Immunotherapy.Frontiers in immunology · 2022Article
- Results from Genetic Studies in Patients Affected with Craniosynostosis: Clinical and Molecular Aspects.Frontiers in molecular biosciences · 2022Article
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Authors and funding
83 authors.
Christopher C Y MakDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
Dan DohertyDepartment of Pediatrics, University of Washington, Seattle, WA, USA.
Angela E LinMedical Genetics, MassGeneral Hospital for Children, Boston, MA, USA.
Nancy VegasLaboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.
Megan T ChoGeneDx, Gaithersburg, MD, USA.
Géraldine ViotGynécologie Obstétrique, Hôpital Cochin, Hôpitaux Universitaires Paris Centre (HUPC), Assistance Publique Hôpitaux de Paris (AP-HP), Paris, France.
Clémantine DimartinoLaboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.
James D Weisfeld-AdamsSection of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado-Denver School of Medicine, Aurora, CO, USA.
Davor LesselInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Shelagh JossWest of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow, UK.
Chumei LiMcMaster University Medical Center, Hamilton, Ontario, Canada.
Claudia Gonzaga-JaureguiRegeneron Genetics Center, Regeneron Pharmaceuticals Inc, Tarrytown, NY, USA.
Yuri A ZarateSection of Genetics and Metabolism, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA.
Nadja EhmkeInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Denise HornInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Caitlin TroyerPediatrics and Medical Genetics, University of Virginia Health System, Charlottesville, VA, USA.
Sarina G KantDepartment of Clinical Genetics, Leiden University Medical Center, RC Leiden, The Netherlands.
Youngha LeeDepartment of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Gisele E IshakCenter for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.
Gordon LeungDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
Amanda Barone PritchardDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sandra YangGeneDx, Gaithersburg, MD, USA.
Eric G BendGreenwood Genetic Center, Greenwood, SC, USA.
Francesca FilippiniLaboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.
Chelsea RoadhouseMcMaster University Medical Center, Hamilton, Ontario, Canada.
Nicolas LebrunInstitut Cochin, INSERM U1016, CNRS UMR, Paris Descartes University, Paris, France.
Michele G MehaffeyDepartment of Pediatrics, University of Washington, Seattle, WA, USA.
Pierre-Marie MartinInstitute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Benjamin AppleSection of Clinical Genetics and Metabolism, Department of Pediatrics, University of Colorado-Denver School of Medicine, Aurora, CO, USA.
Francisca MillanGeneDx, Gaithersburg, MD, USA.
Oliver PukPraxis für Humangenetik Tübingen, Tübingen, Germany.
Mariette J V HofferDepartment of Clinical Genetics, Leiden University Medical Center, RC Leiden, The Netherlands.
Lindsay B HendersonGeneDx, Gaithersburg, MD, USA.
Ruth McGowanWest of Scotland Regional Genetics Service, Queen Elizabeth University Hospital, Glasgow, UK.
Ingrid M WentzensenGeneDx, Gaithersburg, MD, USA.
Steven PeiDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
Farah R ZahirDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Mullin YuDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
William T GibsonDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Ann SemanDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Marcie SteevesMedical Genetics, MassGeneral Hospital for Children, Boston, MA, USA.
Jill R MurrellDivision of Genomic Diagnostics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Sabine LuettgenInstitute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Elizabeth FranciscoeviCore healthcare, Bluffton, SC, USA.
Tim M StromInstitute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany.
Louise Amlie-WolfDivision of Medical Genetics, A I duPont Hospital for Children/Nemours, Wilmington, DE, USA.
Angela M KaindlCharité - Universitätsmedizin Berlin, Institute of Neuroanatomy and Cell Biology, Department of Pediatric Neurology and Center for Chronically Sick Children, Berlin, Germany.
William G WilsonPediatrics and Medical Genetics, University of Virginia Health System, Charlottesville, VA, USA.
Sara HalbachDepartment of Human Genetics, University of Chicago, Chicago, IL, USA.
Lina Basel-SalmonRaphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
Noa Lev-ElRaphael Recanati Genetic Institute, Rabin Medical Center-Beilinson Hospital, Petach Tikva, Israel.
Jonas DeneckeDepartment of Pediatrics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
Lisenka E L M VissersDepartment of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, HB Nijmegen, The Netherlands.
Kelly RadtkeClinical Genomics Department, Ambry Genetics, Aliso Viejo, CA, USA.
Jamel ChellyLaboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Nouvel Hôpital Civil, Strasbourg, France.
Elaine ZackaiDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Jan M FriedmanDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Michael J BamshadDepartment of Pediatrics, University of Washington, Seattle, WA, USA.
Deborah A NickersonDepartment of Genome Sciences, University of Washington, Seattle, WA, USA.
University of Washington Center for Mendelian Genomics
Russell R ReidDepartment of Surgery, Section of Plastic Surgery, University of Chicago, Chicago, IL, USA.
Koenraad DevriendtDepartment of Human Genetics, Katholieke Universiteit Leuven, 3000 Leuven, Belgium.
Jong-Hee ChaeDepartment of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea.
Elliot StolermanGreenwood Genetic Center, Greenwood, SC, USA.
Carey McDougallDivision of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Zöe PowisClinical Genomics Department, Ambry Genetics, Aliso Viejo, CA, USA.
Thierry BienvenuInstitut Cochin, INSERM U1016, CNRS UMR, Paris Descartes University, Paris, France.
Tiong Y TanVictorian Clinical Genetics Services, Murdoch Children's Research Institute, Department of Paediatrics, University of Melbourne, Melbourne, 3052, Australia.
Naama OrensteinPediatric Genetics Clinic, Schneider Children's Medical Center of Israel, Petach Tikva, Israel.
William B DobynsDepartment of Pediatrics, University of Washington, Seattle, WA, USA.
Joseph T ShiehInstitute for Human Genetics, University of California San Francisco, San Francisco, CA, USA.
Murim ChoiDepartment of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea.
Darrel WaggonerDepartment of Human Genetics, University of Chicago, Chicago, IL, USA.
Karen W GrippDivision of Medical Genetics, A I duPont Hospital for Children/Nemours, Wilmington, DE, USA.
Michael J ParkerSheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield S10 2TH, UK.
Joan StolerDivision of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
Stanislas LyonnetLaboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.
Valérie Cormier-DaireParis Descartes-Sorbonne Paris Cité University, Institut Imagine, Paris, France.
David ViskochilDivision of Medical Genetics, University of Utah, Salt Lake City, UT, USA.
Trevor L HoffmanSouthern California Kaiser Permanente Medical Group, Anaheim, CA, USA.
Jeanne AmielLaboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.
Brian H Y ChungDepartment of Paediatrics and Adolescent Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
Christopher T GordonLaboratory of Embryology and Genetics of Human Malformation, Institut National de la Santé et de la Recherche Médicale (INSERM) UMR 1163, Institut Imagine, Paris, France.
Funding
Sharing Aggregate Genomics Research Findings with Diverse Participants: A Pilot Study of an Innovative Design StrategyU01HG009599 · NHGRI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI KOENIG, BARBARA A., KWOK, PUI-YAN · 2017 to 2021
$16.3MUW Center for Mendelian GenomicsUM1HG006493 · NHGRI · UNIVERSITY OF WASHINGTON · PI BAMSHAD, MICHAEL JOSEPH, LEAL, SUZANNE M · 2016 to 2020
$15.3MThe Genetic Basis of Mid-Hindbrain MalformationsR01NS050375 · NINDS · UNIVERSITY OF MINNESOTA · PI DOBYNS, WILLIAM B. · 2005 to 2019
$9.9MIntellectual and Developmental Disabilities Research CenterU54HD083091 · NICHD · UNIVERSITY OF WASHINGTON · PI DOHERTY, DANIEL · 2014 to 2019
$7.9MNHGRI Genome Sequencing Program Coordinating CenterU24HG008956 · NHGRI · RUTGERS, THE STATE UNIV OF N.J. · PI BUYSKE, STEVEN G, MATISE, TARA C. · 2016 to 2020
$4.9MNHGRI NIH HHS U01 HG009599NHGRI NIH HHS U24 HG008956NHGRI NIH HHS UM1 HG006493NICHD NIH HHS U54 HD083091NINDS NIH HHS R01 NS050375Wellcome Trust
Abstract
MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295* observed in 8/21 probands, fall in the terminal exon or the extreme 3' region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.
Indexed as
Abnormalities, MultipleAdolescentBasilar ArteryCarotid ArteriesCerebellar VermisCerebellumChildChild, PreschoolCohort StudiesComparative Genomic HybridizationCraniofacial AbnormalitiesExome SequencingFemaleFibroblastsHumansImaging, Three-DimensionalMN1 protein, humanTrans-ActivatorsTumor Suppressor Proteinscraniofacial developmentintellectual disabilityMCTT syndromeMN1rhombencephalosynapsis
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