ArticleAmerican journal of human genetics2023
Rare EIF4A2 variants are associated with a neurodevelopmental disorder characterized by intellectual disability, hypotonia, and epilepsy.
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Article in American journal of human genetics, 2023. 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 16 papers.
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16 citing papers in PubMed, 29 citations in OpenAlex.
- Reduction of forebrain interneurons alters cellular organization and cortical neurogenesis in a mouse model of X-linked intellectual disability.bioRxiv : the preprint server for biology · 2026Article
- Structural variations in evolutionary novel genomic regions: new insights into neurodevelopmental disorders by long-read DNA Sequencing.Molecular medicine (Cambridge, Mass.) · 2026Article
- Nonsense-mediated mRNA decay and associated splicing patterns in neurodevelopmental disorders.Frontiers in molecular biosciences · 2026Review
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- Epigenetic, ribosomal, and immune dysregulation in paediatric acute-onset neuropsychiatric syndrome.Molecular psychiatry · 2025Article
- De novo and inherited variants in DDX39B cause a novel neurodevelopmental syndrome.Brain : a journal of neurology · 2025Article
- Lens Proteomics Provide Novel Clues for Cataractogenesis: Original Investigation and a Broad Literature Survey.Journal of clinical medicine · 2025Article
- DEAD/DEAH-box RNA helicases shape the risk of neurodevelopmental disorders.Trends in genetics : TIG · 2025Review
- Identification of Immune-Related Biomarkers of Schizophrenia in the Central Nervous System Using Bioinformatic Methods and Machine Learning Algorithms.Molecular neurobiology · 2025Article
- Changes in RNA Splicing: A New Paradigm of Transcriptional Responses to Probiotic Action in the Mammalian Brain.Microorganisms · 2025Article
- Reciprocal chromosome translocation t(3;4)(q27;q31.2) with deletion of 3q27 and reduced FBXW7 expression in a patient with developmental delay, hypotonia, and seizures.Journal of human genetics · 2024Article
- Amyotrophic Lateral Sclerosis-Associated Mutants of SOD1 Perturb mRNA Splicing through Aberrant Interactions with SRSF2.Analytical chemistry · 2024Article
- The role of DEAD- and DExH-box RNA helicases in neurodevelopmental disorders.Frontiers in molecular neuroscience · 2024Review
- RNA binding proteins in cardiovascular development and disease.Current topics in developmental biology · 2024Article
- Exploring the targeting spectrum of rocaglates among eIF4A homologs.RNA (New York, N.Y.) · 2023Article
Corrections and comments
- Erratum issued
Authors and funding
47 authors at 20 institutions in 9 countries.
Maimuna S PaulDepartment of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA.
Anna R DuncanDivision of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Neonatology and Newborn Medicine, Massachusetts General Hospital for Children, Boston, MA, USA.
Casie A GenettiDivision of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.
Hongling PanJan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
Adam JacksonDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Patricia E GrantDivision of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Department of Radiology, Boston Children's Hospital, Boston, MA, USA.
Jiahai ShiDepartment of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Michele PinelliTelethon Institute of Genetics and Medicine, Pozzuoli, Italy; Department of Translational Medicine, University of Naples "Federico II", Naples, Italy.
Nicola Brunetti-PierriTelethon Institute of Genetics and Medicine, Pozzuoli, Italy; Department of Translational Medicine, University of Naples "Federico II", Naples, Italy.
Alexandra Garza-FloresDepartment of Clinical Genetics, Cook Children's Hospital, Fort Worth, TX, USA.
Dave ShahaniDepartment of Neurology and Epileptology, Cook Children's Hospital, Fort Worth, TX 76104, USA.
Russell P SanetoNeuroscience Institute, Center for Integrative Brain Research, Departments of Pediatric Neurology and Neurology Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
Giuseppe ZampinoCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy; Catholic University of the Sacred Heart, Faculty of Medicine and Surgery, Rome, Italy.
Chiara LeoniCenter for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli, Rome, Italy.
Emanuele AgoliniLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Antonio NovelliLaboratory of Medical Genetics, Translational Cytogenomics Research Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
Ulrike BlümleinDepartment of Pediatrics, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany.
Tobias B HaackInstitute of Human Genetics, Technical University of Munich, 81675 Munich, Germany; Institute of Medical Genetics and Applied Genomics, University of Tuebingen, 72076 Tuebingen, Germany.
Wolfram HeinritzPraxis für Humangenetik Cottbus, 03048 Cottbus, Germany.
Eva MatzkerDepartment of Pediatrics, Carl-Thiem-Klinikum Cottbus, Cottbus, Germany.
Bader AlhaddadInstitute of Human Genetics, Technical University of Munich, 81675 Munich, Germany.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
Tobias BartolomaeusInstitute of Human Genetics, University of Leipzig Medical Center, 04103 Leipzig, Germany.
Saber AlHamdanAl Qrayya, Syria.
Raphael CarapitoLaboratoire 'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), ITI TRANSPLANTEX NG, Université de Strasbourg, 67085 Strasbourg, France; Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital, 67091, Strasbourg, France.
Bertrand IsidorService de Génétique Médicale, Hôpital Hôtel-Dieu, Centre Hospitalier Universitaire de Nantes, Nantes, France.
Seiamak BahramLaboratoire 'ImmunoRhumatologie Moléculaire, Plateforme GENOMAX, INSERM UMR_S 1109, Faculté de Médecine, Fédération Hospitalo-Universitaire OMICARE, Fédération de Médecine Translationnelle de Strasbourg (FMTS), ITI TRANSPLANTEX NG, Université de Strasbourg, 67085 Strasbourg, France; Service d'Immunologie Biologique, Plateau Technique de Biologie, Pôle de Biologie, Nouvel Hôpital Civil, Hôpitaux Universitaires de Strasbourg, 1 Place de l'Hôpital, 67091, Strasbourg, France.
Alyssa RitterDivision of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Kosuke IzumiDivision of Human Genetics, Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Ben Pode ShakkedPediatric Neurology Department, The Edmond and Lilly Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Ortal BarelPediatric Neurology Department, The Edmond and Lilly Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel.
Bruria Ben ZeevPediatric Neurology Department, The Edmond and Lilly Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
Amber BegtrupClinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA.
Deanna Alexis CarereClinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA.
Sureni V MullegamaClinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA.
Timothy Blake PalculictClinical Genomics Program, GeneDx, Gaithersburg, MD 20877, USA.
Daniel G CalameSection of Pediatric Neurology and Developmental Neurosciences, Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Katharina SchwanKaiser Permanente, San Francisco, CA, USA.
Alicia R P AycinenaKaiser Permanente, San Francisco, CA, USA.
Rasa TrabergDepartment of Genetics and Molecular Medicine, Hospital of Lithuanian University of Health Sciences Kauno klinikos, Kaunas, Lithuania.
Genomics England Research Consortium
Sofia DouzgouDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK; Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway.
Harrison PirtDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK.
Naila IsmayilovaDepartment of Paediatric Neurology, Chelsea and Westminster NHS Foundation Trust, London, UK.
Siddharth BankaDivision of Evolution, Infection and Genomics, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester M13 9WL, UK; Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK.
Hsiao-Tuan ChaoDepartment of Pediatrics, Division of Neurology and Developmental Neuroscience, Baylor College of Medicine, Houston, TX, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA; Texas Children's Hospital, Houston, TX, USA; Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA; McNair Medical Institute, The Robert and Janice McNair Foundation, Houston, TX, USA. Electronic address: hc140077@bcm.edu.
Pankaj B AgrawalDivision of Newborn Medicine, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; Division of Genetics and Genomics, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA; The Manton Center for Orphan Disease Research, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA. Electronic address: pankaj.agrawal@enders.tch.harvard.edu.
Boston Children's Hospital · USGenomics (United Kingdom) · GBAgostino Gemelli University Polyclinic · ITBambino Gesù Children's Hospital · ITBaylor College of Medicine · USCarl-Thiem-Klinikum Cottbus · DEChildren's Hospital of Philadelphia · USCook Children's Medical Center · USEdmond and Lily Safra Children's Hospital · ILKaiser Permanente San Francisco Medical Center · USLeipzig University · DETechnical University of Munich · DETexas Children's Hospital · USCentre Hospitalier Universitaire de Nantes · FRChelsea and Westminster Hospital NHS Foundation Trust · GBHarvard University · USHôpitaux Universitaires de Strasbourg · FRHospital of Lithuanian University of Health Sciences Kaunas Clinics · LTInserm · FRNational University of Singapore · SG
Funding
Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5MMEDICAL GENETICS RESEARCH FELLOWSHIP PROGRAMT32GM007526 · NIGMS · BAYLOR COLLEGE OF MEDICINE · PI Brendan Lee · 1985 to 2026
$11.4MGenetic Analysis and Manipulation Core (GAEC)P50HD105351 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI SCOTT Loren POMEROY, MUSTAFA SAHIN · 2021 to 2026
$9.4MMouse Neurodevelopmental Behavior CoreU54HD090255 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI POMEROY, SCOTT LOREN · 2016 to 2020
$5.2MVIGOR: Virtual Genome Center for Infant HealthR01HG011798 · NHGRI · BOSTON CHILDREN'S HOSPITAL · PI AGRAWAL, PANKAJ B, PARKER, MARGARET GRAHAM KEMPER · 2021 to 2025
$5.1MNeonatal Research Training ProgramT32HD098061 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI Stella Kourembanas, Martha C. Sola-Visner · 2019 to 2026
$4.0MA powerful web-based discovery platform for rare disease geneticsR01HG009141 · NHGRI · BROAD INSTITUTE, INC. · PI QUINLAN, AARON R, REHM, HEIDI L · 2017 to 2020
$2.9MTranslational Post-doctoral Training in NeurodevelopmentT32MH112510 · NIMH · BOSTON CHILDREN'S HOSPITAL · PI DAVID C GLAHN, CHARLES Alexander NELSON · 2017 to 2026
$2.6MSPEG is Critical in Skeletal Muscle Development and FunctionR01AR068429 · NIAMS · BOSTON CHILDREN'S HOSPITAL · PI AGRAWAL, PANKAJ B · 2015 to 2019
$1.9MNHGRI NIH HHS R01 HG009141NHGRI NIH HHS R01 HG011798NHGRI NIH HHS UM1 HG008900NIAMS NIH HHS R01 AR068429NICHD NIH HHS P50 HD105351NICHD NIH HHS T32 HD098061NICHD NIH HHS U54 HD090255NIGMS NIH HHS T32 GM007526NIMH NIH HHS T32 MH112510Wellcome Trust
Abstract
Eukaryotic initiation factor-4A2 (EIF4A2) is an ATP-dependent RNA helicase and a member of the DEAD-box protein family that recognizes the 5' cap structure of mRNAs, allows mRNA to bind to the ribosome, and plays an important role in microRNA-regulated gene repression. Here, we report on 15 individuals from 14 families presenting with global developmental delay, intellectual disability, hypotonia, epilepsy, and structural brain anomalies, all of whom have extremely rare de novo mono-allelic or inherited bi-allelic variants in EIF4A2. Neurodegeneration was predominantly reported in individuals with bi-allelic variants. Molecular modeling predicts these variants would perturb structural interactions in key protein domains. To determine the pathogenicity of the EIF4A2 variants in vivo, we examined the mono-allelic variants in Drosophila melanogaster (fruit fly) and identified variant-specific behavioral and developmental defects. The fruit fly homolog of EIF4A2 is eIF4A, a negative regulator of decapentaplegic (dpp) signaling that regulates embryo patterning, eye and wing morphogenesis, and stem cell identity determination. Our loss-of-function (LOF) rescue assay demonstrated a pupal lethality phenotype induced by loss of eIF4A, which was fully rescued with human EIF4A2 wild-type (WT) cDNA expression. In comparison, the EIF4A2 variant cDNAs failed or incompletely rescued the lethality. Overall, our findings reveal that EIF4A2 variants cause a genetic neurodevelopmental syndrome with both LOF and gain of function as underlying mechanisms.
Indexed as
Drosophila ProteinsEpilepsyIntellectual DisabilityNeurodevelopmental DisordersAnimalsDEAD-box RNA HelicasesDrosophilaDrosophila melanogasterEukaryotic Initiation Factor-4AHumansMuscle HypotoniaRNA, MessengerDEAD-box RNA Helicasesdpp protein, DrosophilaDrosophila ProteinsEIF4A2 protein, humaneIF4A protein, DrosophilaEukaryotic Initiation Factor-4ARNA, MessengerDEAD-box proteinDrosophilaepilepsyneurodevelopmental disordertranscription factor
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