Heterozygous loss-of-function DHX9 variants are associated with neurodevelopmental disorders: Human genetic and experimental evidences |
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| Institution: | 1. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan;2. Brain Research Institute, Niigata University, Niigata, Japan;3. Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan;4. Mouse Phenotype Analysis Division, RIKEN BioResource Research Center, Tsukuba, Ibaraki, Japan;5. Experimental Animal Division, RIKEN BioResource Research Center, Tsukuba, Ibaraki, Japan;6. Cell Architecture Laboratory, National Institute of Genetics, Mishima, Shizuoka, Japan;7. Mammalian Development Laboratory, Department of Gene Function and Phenomics, National Institute of Genetics, Mishima, Shizuoka, Japan;8. Department of Medical Genetics, Osaka Women''s and Children''s Hospital, Osaka, Japan;1. Diagnostics Division, Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, 500039, India;2. Graduate Studies, Regional Centre for Biotechnology, Faridabad, Haryana, India;3. Graduate Studies, Manipal Academy of Higher Education, Manipal, Karnataka, India;4. Department of Radiology, Mazumdar Shaw Medical Centre, Narayana Hrudayalaya Hospitals, Bangalore, India;5. Division of Medical Genetics, Mazumdar Shaw Medical Centre, Narayana Hrudayalaya Hospitals, Bangalore, India;1. Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan;2. Laboratory for Sensory Circuit Formation, Riken Center for Developmental Biology, Kobe 650-0047, Japan;3. Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan;4. Department of Developmental Biology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan;5. Institute of Biomedical Science, Kansai Medical University, Hirakata 573-1010, Japan;6. PRESTO and CREST, Japan Science and Technology Agency (JST), Saitama 332-0012, Japan;1. Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium;2. Melbourne Law School, University of Melbourne, Melbourne, Australia;3. Murdoch Children''s Research Institute, Melbourne, Australia;1. Neuroscience Department, Meyer Children’s Hospital IRCCS, Florence, Italy;2. University of Florence, Florence, Italy;3. Department of Neuroscience, Psychology, Drug Research and Child Health (NeuroFarBa), Section of Pharmacology and Toxicology, University of Florence, Florence, Italy;4. Newcastle University Translational and Clinical Research Institute, Newcastle upon Tyne, UK;5. Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK;6. Department of Neurology and Institute of Human Genetics and Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA;7. National Enterprise for NanoScience and NanoTechnology (NEST), Istituto Nanoscienze, Consiglio Nazionale delle Ricerche (CNR) and Scuola Normale Superiore Pisa, Pisa, Italy;8. Division of Metabolic Disorders, Children’s Hospital of Orange County (CHOC), Orange, CA, USA;9. Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia;10. Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands;11. Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany;12. Department of Pediatric Neurology and Developmental Medicine, Dr. v. Hauner Children’s Hospital, LMU - University of Munich, München, Germany;13. William Harvey Research Institute, Queen Mary University of London, London, UK;14. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;15. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama 236-0004 Japan;16. Department of Neurology, The Children’s Hospital at Westmead and the Children’s Hospital at Westmead Clinical School, University of Sydney, Westmead NSW, Australia;17. Sorbonne Université, Institut du Cerveau - Paris Brain Institute - ICM, Inserm, CNRS, Paris, France;18. Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Génétique, DMU BioGeM, Paris, France;19. Northern Genetics Service, Newcastle upon Tyne hospitals NHS Foundation Trust, Newcastle, UK;20. New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW 2031, Australia;21. Neuroscience Research Australia, Sydney, NSW 2031, Australia;22. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy;23. Institute for Transition, Rehabilitation and Palliation, Paracelsus Medical University, Salzburg, Austria;24. Department of Precision Medicine, University “Luigi Vanvitelli,” Naples, Italy;25. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy;26. Department of Child Neurology, Nishi-Niigata Chuo National Hospital, Niigata 950-2085, Japan;27. Department for Child Health and Human Development, Saitama Children’s Medical Center, Saitama 330-8777, Japan;28. Department of Biochemistry, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan;29. School of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan;30. Brain Research Institute, Niigata University, Niigata 951-8585, Japan;31. Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands;32. Centre de référence Maladies Rares “Déficience intellectuelle de cause rare,” Sorbonne Université, Paris, France;33. Département de Neuropédiatrie, Hôpital Armand Trousseau, APHP, Sorbonne Université, Paris, France;34. Department of Neurosciences, Queensland Children’s Hospital, Brisbane QLD, Australia;35. Centre for Advanced Imaging, University of Queensland, St Lucia QLD, Australia;36. Department of Pediatrics, Showa University School of Medicine, Tokyo 142-8666, Japan;37. Istituto Neuroscienze CNR, Padova, Italy;1. Department of Hematology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China;1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA;2. Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital, Houston, TX 77030, USA;3. Center for Individualized Medicine, Mayo Clinic, Rochester, MN 55905, USA;4. Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy;5. Division of Genetics and Metabolism, University of Kentucky, Lexington, KY, USA;6. Section of Genetics and Metabolism, University of Arkansas for Medical Sciences, Little Rock, AR, USA;7. Division of Genetics and Genomic Medicine, Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA;8. Edward Mallinckrodt Department of Pediatrics, Washington University in St. Louis School of Medicine and St. Louis Children’s Hospital, St. Louis, Missouri, USA;9. Laboratory of Molecular Genetics, CHU de Nantes, Nantes, France;10. Department of Medical Genetics, CHU de Poitiers, Poitiers, France;11. Department of Biochemistry and Biophysics, Center for RNA Biology, University of Rochester School of Medicine, Rochester, NY 14642, USA;12. Division of Genetics and Genomics, and Howard Hughes Medical Institute, Boston Children’s Hospital, and Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA;13. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;14. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA;15. The Raphael Recanati Genetic Institute, Rabin Medical Center, Petach Tikva, Israel;16. Cancer Research Center, Chaim Sheba Medical Center, Ramat Gan, Israel;17. Medical Genetics Institute of Maccabi HMO, Rechovot, Israel;18. Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA;19. Department of Clinical Genomics, Mayo Clinic, Rochester, MN 55905, USA;20. APHP, Département de génétique, Sorbonne Université, GRC n°19, ConCer-LD, Centre de Référence déficiences intellectuelles de causes rares, Hôpital Armand Trousseau, 75012 Paris, France;21. APHP. SU, Centre de Référence Malformations et maladies congénitales du cervelet, département de génétique et embryologie médicale, Hôpital Trousseau, 75012 Paris, France;22. Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health, London, UK;23. Department of Neurology, Great Ormond Street Hospital for Children, London, UK;24. Institute for Clinical Genetics, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany;25. Unit of Neuromuscular and Neurodegenerative Disorders, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy;26. Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030, USA |
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| Abstract: | DExH-box helicases are involved in unwinding of RNA and DNA. Among the 16 DExH-box genes, monoallelic variants of DHX16, DHX30, DHX34, and DHX37 are known to be associated with neurodevelopmental disorders. In particular, DHX30 is well established as a causative gene for neurodevelopmental disorders. Germline variants of DHX9, the closest homolog of DHX30, have not been reported until now as being associated with congenital disorders in humans, except that one de novo heterozygous variant, p.(Arg1052Gln) of the gene was identified during comprehensive screening in a patient with autism; unfortunately, the phenotypic details of this individual are unknown. Herein, we report a patients with a heterozygous de novo missense variant, p.(Gly414Arg) of DHX9 who presented with a short stature, intellectual disability, and ventricular non-compaction cardiomyopathy. The variant was located in the glycine codon of the ATP-binding site, G-C-G-K-T. To assess the pathogenicity of these variants, we generated transgenic Drosophila lines expressing human wild-type and mutant DHX9 proteins: 1) the mutant proteins showed aberrant localization both in the nucleus and the cytoplasm; 2) ectopic expression of wild-type protein in the visual system led to the rough eye phenotype, whereas expression of the mutant proteins had minimal effect; 3) overexpression of the wild-type protein in the retina led to a reduction in axonal numbers, whereas expression of the mutant proteins had a less pronounced effect. Furthermore, in a gene-editing experiment of Dhx9 G416 to R416, corresponding to p.(Gly414Arg) in humans, heterozygous mice showed a reduced body size, reduced emotionality, and cardiac conduction abnormality. In conclusion, we established that heterozygosity for a loss-of-function variant of DHX9 can lead to a new neurodevelopmental disorder. |
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| Keywords: | DHX9 Neurodevelopmental disorder MeDUsA WT"} {"#name":"keyword" "$":{"id":"kwrd0030"} "$$":[{"#name":"text" "_":"wild-type UAS"} {"#name":"keyword" "$":{"id":"kwrd0040"} "$$":[{"#name":"text" "_":"Upstream Activating Sequence REP"} {"#name":"keyword" "$":{"id":"kwrd0050"} "$$":[{"#name":"text" "_":"rough-eye phenotype MeDUsA"} {"#name":"keyword" "$":{"id":"kwrd0060"} "$$":[{"#name":"text" "_":"method for the quantification of degeneration using fly axons |
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