Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy |
| |
| Affiliation: | 1. Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan;2. Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan;3. Department of Child Neurology, National Center Hospital, National Center of Neurology and Psychiatry, Tokyo, Japan;4. Department of Pediatric Neurology, Miyagi Children’s Hospital, Sendai, Japan;5. Department of Pediatrics, Tohoku University Hospital, Tohoku University, Sendai, Japan;6. Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan;7. Department of Neurology, Kanagawa Children’s Medical Center, Yokohama, Japan;8. Division of Medical Genetics, Kanagawa Children’s Medical Center, Yokohama, Japan;9. Department of Pediatrics, Jichi Medical University, Tochigi, Japan;10. Department of Child Neurology, NHO Nishiniigata Chuo Hospital, Niigata, Japan;11. Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Izumi, Japan;12. Department of Neuropediatrics, Tokyo Metropolitan Neurological Hospital, Tokyo, Japan;13. Department of Pediatric Neurology, Children’s Medical Center, Osaka City General Hospital, Osaka, Japan;14. Department of Pediatrics, Tokyo Metropolitan Higashiyamato Medical Center for Developmental/Multiple Disabilities, Tokyo, Japan;15. Department of Pediatric Neurology, Seirei-Mikatahara General Hospital, Hamamatsu, Japan;16. Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan;17. Division of Neurology, Nagano Children’s Hospital, Azumino, Nagano, Japan;18. Division of Rehabilitation, Nagano Children’s Hospital, Azumino, Nagano, Japan;19. Department of Pediatrics and Neonatology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan;20. Department of Pediatrics, Tsuchiura Kyodo General Hospital, Ibaraki, Japan;21. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan;22. Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan;23. Department of Pediatrics and Child Health, Kurume University School of Medicine, Kurume, Japan;24. Department of Pediatrics, Fukuoka University Faculty of Medicine, Fukuoka, Japan;25. Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan;26. Department of Pediatrics, School of Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan;27. Department of Pediatrics, Graduate School of Medicine, Gunma University, Gunma, Japan;28. Department of Pediatric Neurology, Aichi Developmental Disability Center Central Hospital, Aichi, Japan;29. Department of Pediatrics, School of Medicine, Tokyo Women’s Medical University, Tokyo, Japan;30. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan;31. Department of Pediatrics, School of Medicine, Iwate Medical University, Iwate, Japan;32. Department of Pediatrics, Matsudo City General Hospital, Matsudo, Japan;33. Department of Pediatrics, Nara Medical University, Nara, Japan;34. Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan;35. Department of Neonatology, Mie Chuo Medical Center, National Hospital Organization, Tsu, Japan;36. Department of Pediatrics, Mie University School of Medicine, Mie, Japan;37. Department of Pediatric Genetics, S.B.Ü. Dr. Behçet Uz Children’s Education and Research Hospital, Izmir, Turkey;38. Department of Pediatric Genetics, Faculty of Medicine, Dokuz Eylul University, Izmir, Turkey;39. Unidade de Genética Clínica, Instituto da Criança do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil;40. Department of Genetics, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia;41. Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan;42. Department of Rare Disease Genomics, Yokohama City University Hospital, Yokohama, Japan;43. RIKEN Center for Advanced Intelligence Project, Tokyo, Japan;44. Department of Clinical Genetics, Yokohama City University Hospital, Yokohama, Japan;45. Department of Human Genetics, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan;1. Faculty of Medicine, University of Southampton, Southampton, United Kingdom;2. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA;3. Center for Genomic Medicine, Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA;4. Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA;1. NIH Undiagnosed Diseases Program, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD;2. Office of Strategic Coordination, Office of the Director, National Institutes of Health, Bethesda, MD;1. Department of Neurology, School of Medicine, University of Sao Paulo, Sao Paulo, Brazil;2. Molecular Neurogenomics Group, VIB-UAntwerp Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium;3. Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium;4. Medical Department, Mendelics Genomic Analysis, Sao Paulo, Brazil;1. Department of Human Genetics, KU Leuven, Leuven, Belgium;2. Department of Clinical and Molecular Genetics, Vall d’Hebron University Hospital and Medicine Genetics Group, Vall d’Hebron Research Institute, Barcelona, Spain;3. Medical Genetics Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy;4. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy;5. Centre for Developmental Disabilities, University Hospitals Leuven, Leuven, Belgium;6. Pediatric Neurology Institute, The Edmond & Lily Safra Children’s Hospital, Sheba Medical Center, Ramat Gan, Tel-Hashomer, Israel;7. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel;8. Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, Victoria, Australia;9. Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) de Nantes, Nantes, France;10. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland;11. Greenwood Genetic Center, Greenwood, SC;12. Salpêtrière Hospital Genetic Department and Reference Center for Rare Intellectual Disabilities, APHP, Paris, France;13. Department of Medical Genetics, Hospices Civils de Lyon and NeuroMyogene Institute, CNRS UMR 5310 - INSERM U1217, Université Claude Bernard Lyon 1, Lyon, France;14. Genetic Institute, Barzilai University Medical Center, Ashkelon, Israel;15. Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheba, Israel;16. Department of Neuroscience and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy;17. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada;18. Department of Human Genetics, Emory Clinic, Emory Healthcare, Atlanta, GA;19. Switch Laboratory, VIB-KU Leuven Center for Brain & Disease Research, Leuven, Belgium;20. Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium;21. Genetics Institute, Rambam Health Care Campus, Haifa, Israel;22. Laboratory of Embryology and Genetics of Human Malformations, Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Imagine, Université de Paris, Paris, France;23. Département de Génétique, AP-HP.Sorbonne Université, Hôpital Pitié-Salpêtrière, Paris, France;24. Parenting and Special Education Research Unit, KU Leuven, Leuven, Belgium;25. Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada;26. GeneDx, Inc, Gaithersburg, MD;27. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA;28. Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy;29. Department of Paediatrics, University of Melbourne, Royal Children''s Hospital, Victoria, Australia;30. Florey and Murdoch Children’s Research Institutes, Melbourne, Victoria, Australia;31. Center for Human Genetics, University Hospitals Leuven, Leuven, Belgium;32. Center for Developmental Psychiatry, KU Leuven, Leuven, Belgium;33. Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA;34. Pediatric Neurology Department, Lyon University Hospital, Lyon, France;35. The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel;36. Department of Paediatrics and Child Health, University of Otago, Wellington, New Zealand;37. Center for Pediatric Neurological Disease Research, St. Jude Children’s Research Hospital, Memphis, TN;1. Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN;2. Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN;1. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;2. Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA;3. Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School, Boston, MA |
| |
| Abstract: | PurposeCerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects.MethodsPatients with CBHA in 176 families were genetically examined using exome sequencing. Patients with disease-causing variants were clinically evaluated.ResultsDisease-causing variants were identified in 96 of the 176 families (54.5%). After excluding 6 families, 48 patients from 42 families were categorized as having syndromic associations with CBHA, whereas the remaining 51 patients from 48 families had isolated CBHA. In 51 patients, 26 aberrant genes were identified, of which, 20 (76.9%) caused disease in 1 family each. The most prevalent genes were CACNA1A, ITPR1, and KIF1A. Of the 26 aberrant genes, 21 and 1 were functionally annotated to atrophy and hypoplasia, respectively. CBHA+S was more clinically severe than CBHA–S. Notably, ARG1 and FOLR1 variants were identified in 2 families, leading to medical treatments.ConclusionA wide genetic and clinical diversity of CBHA was revealed through exome sequencing in this cohort, which highlights the importance of comprehensive genetic analyses. Furthermore, molecular-based treatment was available for 2 families. |
| |
| Keywords: | Cerebellar atrophy Cerebellar hypoplasia Disease-causing variants Exome Treatment |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
