Expanding the phenotypic spectrum of ARCN1-related syndrome |
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| Authors: | Alyssa L Ritter Jessica Gold Hiroshi Hayashi Amanda M Ackermann Stephanie Hanke Cara Skraban Sanmati Cuddapah Elizabeth Bhoj Dong Li Yukiko Kuroda Jessica Wen Ryojun Takeda Audrey Bibb Salima El Chehadeh Amélie Piton Jeanine Ohl Mary K Kukolich Keisuke Nagasaki Kosuke Izumi |
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| Institution: | 1. Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA;2. Division of Endocrinology and Diabetes, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA;3. Center for Applied Genomics, The Children''s Hospital of Philadelphia, Philadelphia, PA;4. Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children’s Hospital of Philadelphia, Philadelphia, PA;5. Division of Genetics, Nagano Children’s Hospital, Nagano, Japan;6. Department of Human Genetics, Emory University School of Medicine, Emory University, Atlanta, GA;7. Service de Génétique Médicale, Institut de Génétique Médicale d''Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France;8. Laboratoire de Génétique Médicale, UMR_S1112, Institut de Génétique Médicale d''Alsace (IGMA), Université de Strasbourg et INSERM, Strasbourg, France;9. Department of Translational Medicine and Neurogenetics, Institut Génétique Biologie Moléculaire Cellulaire, IGBMC - CNRS UMR 7104 - Inserm U 1258, Illkirch, France;10. Laboratoire de Diagnostic Génétique, Hôpitaux Universitaires de Strasbourg, Strasbourg, France;11. Service d''assistance Médicale à la Procréation, Centre médico-chirurgical et obstétrical (CMCO), Schiltigheim, France;12. Department of Genetics, Cook Children’s Medical Center, Cook Children''s Health Care System, Fort Worth, TX;13. Department of Pediatrics, Niigata University Medical & Dental Hospital, Niigata, Japan;14. Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan;15. Division of Anatomic Pathology, The Children’s Hospital of Philadelphia, Philadelphia, PA;16. Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children’s Hospital of Philadelphia, Philadelphia, PA;17. Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Duke University School of Medicine, Durham, NC;18. Institute for Genomic Medicine, Columbia University, New York, NY;19. GeneDx, Gaithersburg, MD;20. Department of Medical Genetics, Oslo University Hospital, Oslo, Norway;21. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway;22. Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo, Norway;23. Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, OH;24. Department of Medical Genetics, Children’s Hospital of Eastern Ontario, Ottawa, Ontario, Canada;25. Department of Pediatrics, University Hospital of Muenster, Muenster, Germany;26. Metabolic and Advanced Diagnostics, The Children’s Hospital of Philadelphia, Philadelphia, PA;1. The Comparative Health Outcomes, Policy, and Economics (CHOICE) Institute, Department of Pharmacy, University of Washington, Seattle, WA;2. Department of Biostatistics, Vanderbilt School of Medicine, Vanderbilt University Medical Center, Nashville, TN;3. Department of Health Policy, Vanderbilt School of Medicine, Vanderbilt University Medical Center, Nashville, TN;4. Institute for Public Health Genetics, University of Washington School of Public Health, Seattle, WA;5. Department of Health Policy & Behavioral Sciences, School of Public Health, Georgia State University, Atlanta, GA;6. Genomic Medicine Institute, Geisinger, Danville, PA;7. Department of Population Health Sciences, Geisinger, Danville, PA;8. Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN;1. Health Economics Unit, Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia;2. Australian Genomics Health Alliance, Melbourne, Victoria, Australia;3. Murdoch Children’s Research Institute, Melbourne, Victoria, Australia;4. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Victoria, Australia;5. Department of Pediatrics, University of Melbourne, Melbourne, Victoria, Australia;6. Monash Genetics, Monash Health, Melbourne, Victoria, Australia;7. Department of Pediatrics, Monash University, Melbourne, Victoria, Australia;8. Melbourne Genomics Health Alliance, Melbourne, Victoria, Australia;1. Division of Newborn Medicine, Department of Pediatrics, Boston Children’ Hospital and Harvard Medical School, Boston, MA;2. Division of Genetics & Genomics, Department of Pediatrics, Boston Children’s Hospital and Harvard Medical School, Boston, MA;3. The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA;1. The Institute for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY;2. Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY;3. Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY;4. Department of Psychiatry & Behavioral Sciences, Memorial Sloan Kettering Cancer Center, New York, NY;5. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY;6. Weill Cornell Medical College, New York, NY;1. Cancer Prevention and Control Platform, Moon Shots Program, The University of Texas MD Anderson Cancer Center, Houston, TX;2. Clinical Cancer Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX;3. Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX;4. Research Medical Library, The University of Texas MD Anderson Cancer Center, Houston, TX;1. Centre for Biomedical Ethics and Law, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium;2. Laboratory for Cytogenetics and Genome Research, Department of Human Genetics, KU Leuven, Leuven, Belgium;3. Reproductive Genetics Unit, Center of Human Genetics, UZ Leuven, Leuven, Belgium;4. Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland |
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| Abstract: | PurposeThis study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome.MethodsPatients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient.ResultsIn total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported.ConclusionARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype–phenotype correlations are required. |
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| Keywords: | ARCN1 COPI Micrognathia |
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