Hannah Stamberger1,2, Trine B Hammer3,4, Rikke S Møller3,5, Ingrid E Scheffer6,7,8,9,10, Elena Gardella3,5, Danique R M Vlaskamp1,11,12, Birgitte Bertelsen13, Simone Mandelstam14,15,16,17,18, Iris de Lange19, Jing Zhang20, Candace T Myers21, Christina Fenger3, Zaid Afawi22, Edith P Almanza Fuerte21, Danielle M Andrade23, Yunus Balcik24, Bruria Ben Zeev25,26, Mark F Bennett1,27,28, Samuel F Berkovic1, Bertrand Isidor29, Arjan Bouman30, Eva Brilstra19, Øyvind L Busk31, Anita Cairns32, Roseline Caumes33, Nicolas Chatron34, Russell C Dale35, Christa de Geus36, Patrick Edery34,37, Deepak Gill35, Jacob Bie Granild-Jensen38, Lauren Gunderson39, Boudewijn Gunning40, Gali Heimer25,26, Johan R Helle31, Michael S Hildebrand1,15, Georgie Hollingsworth1, Volodymyr Kharytonov41, Eric W Klee39,42, Bobby P C Koeleman19, David A Koolen43, Christian Korff44, Sébastien Küry29, Gaetan Lesca34, Dorit Lev26,45, Richard J Leventer14,15,16, Mark T Mackay14,15,16, Erica L Macke42, Meriel McEntagart46, Shekeeb S Mohammad35, Pauline Monin34, Martino Montomoli47, Eva Morava39,42, Sebastien Moutton48,49, Alison M Muir21, Elena Parrini47, Peter Procopis35,50, Emmanuelle Ranza51, Laura Reed52, Philipp S Reif24, Felix Rosenow24, Massimiliano Rossi34,37, Lynette G Sadleir53, Tara Sadoway23, Helenius J Schelhaas40, Amy L Schneider1, Krati Shah54, Ruth Shalev55, Sanjay M Sisodiya56, Thomas Smol57, Connie T R M Stumpel58, Kyra Stuurman30, Joseph D Symonds59,60, Frederic Tran Mau-Them61,62, Nienke Verbeek19, Judith S Verhoeven63, Geoffrey Wallace32,64, Keren Yosovich65, Yuri A Zarate66, Ayelet Zerem26,67, Sameer M Zuberi59,60, Renzo Guerrini47, Heather C Mefford21, Chirag Patel68, Yue-Hua Zhang20. 1. Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia. 2. Applied and Translational Neurogenomics group, Center for Molecular Neurology, VIB, and Department of Neurology, University Hospital of Antwerp, University of Antwerp, Antwerpen, Belgium. 3. Department of Epilepsy Genetics, Danish Epilepsy Centre Filadelfia, Dianalund, Denmark. 4. Clinical Genetic Department, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 5. Institute for Regional Health Services Research, University of Southern Denmark, Odense, Denmark. 6. Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au. 7. Royal Children's Hospital, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au. 8. Murdoch Children's Research Institute, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au. 9. Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au. 10. Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au. 11. University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, the Netherlands. 12. University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands. 13. Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 14. Royal Children's Hospital, Melbourne, VIC, Australia. 15. Murdoch Children's Research Institute, Melbourne, VIC, Australia. 16. Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia. 17. Department of Radiology, University of Melbourne, Melbourne, VIC, Australia. 18. Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia. 19. Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands. 20. Department of Pediatrics, Peking University First Hospital, Beijing, China. 21. Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA. 22. Tel Aviv University Medical School, Tel Aviv, Israel. 23. Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada. 24. Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, University Hospital Frankfurt, and Center for Personalized Translational Epilepsy Research (CePTER), Goethe-University Frankfurt, Frankfurt am Main, Germany. 25. Edmond and Lily Safra Children's Hospital, Pediatric Neurology Unit, Tel-Hashomer, Israel. 26. Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel. 27. The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia. 28. Department of Medical Biology University of Melbourne, Melbourne, VIC, Australia. 29. Service de génétique médicale, CHU Nantes, Nantes, France. 30. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands. 31. Section for Medical Genetics, Telemark Hospital, Skien, Norway. 32. Department of Neurosciences, Queensland Children's Hospital, Brisbane, QLD, Australia. 33. Service de Neuropédiatrie, Pôle de Médecine et Spécialités Médicales, CHRU de Lille, Lille, France. 34. Lyon University Hospitals, Departments of Genetics, Lyon, France. 35. T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia. 36. University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands. 37. INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Bron, France. 38. Child and Youth, Randers Regional Hospital, Randers, Denmark. 39. Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA. 40. Stichting Epilepsie Instellingen Nederland, Zwolle, The Netherlands. 41. Clinical Hospital "Psychiatry", Kyiv, Ukraine. 42. Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA. 43. Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands. 44. Pediatric Neurology Unit, University Hospitals, Geneva, Switzerland. 45. Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel. 46. Medical Genetics, St George's University Hospitals NHS FT, Cranmer Tce, London, United Kingdom. 47. Department of Neuroscience, Pharmacology and Child Health, Children's Hospital A. Meyer and University of Florence, Florence, Italy. 48. CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, France. 49. INSERM UMR1231 GAD, FHU-TRANSLAD, Université de Bourgogne, Dijon, France. 50. Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia. 51. Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland. 52. Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. 53. Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand. 54. One Centre of Genetics, Vadodara, India. 55. Neuropaediatric Unit, Shaare Zedek Medical Centre, Hebrew University School of Medicine, Jerusalem, Israel. 56. Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom and Chalfont Centre for Epilepsy, Bucks, UK. 57. Institut de Génétique Médicale, Hopital Jeanne de Flandre, Lille University Hospital, Lille, France. 58. Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands. 59. Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK. 60. College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. 61. UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France. 62. INSERM UMR1231 GAD, Dijon, France. 63. Academic Center for Epileptology, Kempenhaege, Department of Neurology, Heeze, The Netherlands. 64. School of Medicine, University of Queensland, Brisbane, QLD, Australia. 65. Molecular Genetics Lab, Wolfson Medical Center, Holon, Israel. 66. Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA. 67. White Matter Disease Care, Pediatric Neurology Unit, Dana-Dwak Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel. 68. Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
Abstract
PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
PURPOSE: Pathogenic variants in the X-linked gene NEXMIF (previously KIAA2022) are associated with intellectual disability (ID), autism spectrum disorder, and epilepsy. We aimed to delineate the female and male phenotypic spectrum of NEXMIF encephalopathy. METHODS: Through an international collaboration, we analyzed the phenotypes and genotypes of 87 patients with NEXMIF encephalopathy. RESULTS: Sixty-three females and 24 males (46 new patients) with NEXMIF encephalopathy were studied, with 30 novel variants. Phenotypic features included developmental delay/ID in 86/87 (99%), seizures in 71/86 (83%) and multiple comorbidities. Generalized seizures predominated including myoclonic seizures and absence seizures (both 46/70, 66%), absence with eyelid myoclonia (17/70, 24%), and atonic seizures (30/70, 43%). Males had more severe developmental impairment; females had epilepsy more frequently, and varied from unaffected to severely affected. All NEXMIF pathogenic variants led to a premature stop codon or were deleterious structural variants. Most arose de novo, although X-linked segregation occurred for both sexes. Somatic mosaicism occurred in two males and a family with suspected parental mosaicism. CONCLUSION: NEXMIF encephalopathy is an X-linked, generalized developmental and epileptic encephalopathy characterized by myoclonic-atonic epilepsy overlapping with eyelid myoclonia with absence. Some patients have developmental encephalopathy without epilepsy. Males have more severe developmental impairment. NEXMIF encephalopathy arises due to loss-of-function variants.
Entities:
Keywords:
KIAA2022; NEXMIF; developmental and epileptic encephalopathy; epilepsy; intellectual disability
Authors: Elizabeth Langley; Laura S Farach; Mary K Koenig; Hope Northrup; David F Rodriguez-Buritica; Kate Mowrey Journal: Am J Med Genet A Date: 2022-02-10 Impact factor: 2.578