NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Hannah Stamberger^#^{1

2}, Trine B Hammer^#^{3

4}, Elena Gardella^{3

5}, Danique R M Vlaskamp^{1

6

7}, Birgitte Bertelsen⁸, Simone Mandelstam^{9

10

11

12

13}, Iris de Lange¹⁴, Jing Zhang¹⁵, Candace T Myers¹⁶, Christina Fenger³, Zaid Afawi¹⁷, Edith P Almanza Fuerte¹⁶, Danielle M Andrade¹⁸, Yunus Balcik¹⁹, Bruria Ben Zeev^{20

21}, Mark F Bennett^{1

22

23}, Samuel F Berkovic¹, Bertrand Isidor²⁴, Arjan Bouman²⁵, Eva Brilstra¹⁴, Øyvind L Busk²⁶, Anita Cairns²⁷, Roseline Caumes²⁸, Nicolas Chatron²⁹, Russell C Dale³⁰, Christa de Geus³¹, Patrick Edery^{29

32}, Deepak Gill³⁰, Jacob Bie Granild-Jensen³³, Lauren Gunderson³⁴, Boudewijn Gunning³⁵, Gali Heimer^{20

21}, Johan R Helle²⁶, Michael S Hildebrand^{1

10}, Georgie Hollingsworth¹, Volodymyr Kharytonov³⁶, Eric W Klee^{34

37}, Bobby P C Koeleman¹⁴, David A Koolen³⁸, Christian Korff³⁹, Sébastien Küry²⁴, Gaetan Lesca²⁹, Dorit Lev^{21

40}, Richard J Leventer^{9

10

11}, Mark T Mackay^{9

10

11}, Erica L Macke³⁷, Meriel McEntagart⁴¹, Shekeeb S Mohammad³⁰, Pauline Monin²⁹, Martino Montomoli⁴², Eva Morava^{34

37}, Sebastien Moutton^{43

44}, Alison M Muir¹⁶, Elena Parrini⁴², Peter Procopis^{30

45}, Emmanuelle Ranza⁴⁶, Laura Reed⁴⁷, Philipp S Reif¹⁹, Felix Rosenow¹⁹, Massimiliano Rossi^{29

32}, Lynette G Sadleir⁴⁸, Tara Sadoway¹⁸, Helenius J Schelhaas³⁵, Amy L Schneider¹, Krati Shah⁴⁹, Ruth Shalev⁵⁰, Sanjay M Sisodiya⁵¹, Thomas Smol⁵², Connie T R M Stumpel⁵³, Kyra Stuurman²⁵, Joseph D Symonds^{54

55}, Frederic Tran Mau-Them^{56

57}, Nienke Verbeek¹⁴, Judith S Verhoeven⁵⁸, Geoffrey Wallace^{27

59}, Keren Yosovich⁶⁰, Yuri A Zarate⁶¹, Ayelet Zerem^{21

62}, Sameer M Zuberi^{54

55}, Renzo Guerrini⁴², Heather C Mefford¹⁶, Chirag Patel⁶³, Yue-Hua Zhang¹⁵, Rikke S Møller^#^{3

5}, Ingrid E Scheffer^#^{64

65

66

67

68}

Affiliations

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 University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, the Netherlands.
⁷ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
⁸ Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁹ Royal Children's Hospital, Melbourne, VIC, Australia.
¹⁰ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹¹ Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia.
¹² Department of Radiology, University of Melbourne, Melbourne, VIC, Australia.
¹³ Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
¹⁴ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁵ Department of Pediatrics, Peking University First Hospital, Beijing, China.
¹⁶ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
¹⁷ Tel Aviv University Medical School, Tel Aviv, Israel.
¹⁸ Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
¹⁹ 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.
²⁰ Edmond and Lily Safra Children's Hospital, Pediatric Neurology Unit, Tel-Hashomer, Israel.
²¹ Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel.
²² The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
²³ Department of Medical Biology University of Melbourne, Melbourne, VIC, Australia.
²⁴ Service de génétique médicale, CHU Nantes, Nantes, France.
²⁵ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
²⁶ Section for Medical Genetics, Telemark Hospital, Skien, Norway.
²⁷ Department of Neurosciences, Queensland Children's Hospital, Brisbane, QLD, Australia.
²⁸ Service de Neuropédiatrie, Pôle de Médecine et Spécialités Médicales, CHRU de Lille, Lille, France.
²⁹ Lyon University Hospitals, Departments of Genetics, Lyon, France.
³⁰ T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
³¹ University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands.
³² INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Bron, France.
³³ Child and Youth, Randers Regional Hospital, Randers, Denmark.
³⁴ Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
³⁵ Stichting Epilepsie Instellingen Nederland, Zwolle, The Netherlands.
³⁶ Clinical Hospital "Psychiatry", Kyiv, Ukraine.
³⁷ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
³⁸ Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
³⁹ Pediatric Neurology Unit, University Hospitals, Geneva, Switzerland.
⁴⁰ Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel.
⁴¹ Medical Genetics, St George's University Hospitals NHS FT, Cranmer Tce, London, United Kingdom.
⁴² Department of Neuroscience, Pharmacology and Child Health, Children's Hospital A. Meyer and University of Florence, Florence, Italy.
⁴³ CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, France.
⁴⁴ INSERM UMR1231 GAD, FHU-TRANSLAD, Université de Bourgogne, Dijon, France.
⁴⁵ Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
⁴⁶ Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
⁴⁷ Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁴⁸ Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand.
⁴⁹ One Centre of Genetics, Vadodara, India.
⁵⁰ Neuropaediatric Unit, Shaare Zedek Medical Centre, Hebrew University School of Medicine, Jerusalem, Israel.
⁵¹ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom and Chalfont Centre for Epilepsy, Bucks, UK.
⁵² Institut de Génétique Médicale, Hopital Jeanne de Flandre, Lille University Hospital, Lille, France.
⁵³ Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
⁵⁴ Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK.
⁵⁵ College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁵⁶ UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
⁵⁷ INSERM UMR1231 GAD, Dijon, France.
⁵⁸ Academic Center for Epileptology, Kempenhaege, Department of Neurology, Heeze, The Netherlands.
⁵⁹ School of Medicine, University of Queensland, Brisbane, QLD, Australia.
⁶⁰ Molecular Genetics Lab, Wolfson Medical Center, Holon, Israel.
⁶¹ Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA.
⁶² White Matter Disease Care, Pediatric Neurology Unit, Dana-Dwak Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
⁶³ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
⁶⁴ Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.
⁶⁵ Royal Children's Hospital, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.
⁶⁶ Murdoch Children's Research Institute, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.
⁶⁷ Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.
⁶⁸ Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.

^# Contributed equally.

PMID: 33144681
DOI: 10.1038/s41436-020-00988-9

Free article

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Hannah Stamberger et al. Genet Med. 2021 Feb.

Free article

. 2021 Feb;23(2):363-373.

doi: 10.1038/s41436-020-00988-9. Epub 2020 Nov 4.

Authors

Affiliations

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 University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, the Netherlands.
⁷ University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
⁸ Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
⁹ Royal Children's Hospital, Melbourne, VIC, Australia.
¹⁰ Murdoch Children's Research Institute, Melbourne, VIC, Australia.
¹¹ Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia.
¹² Department of Radiology, University of Melbourne, Melbourne, VIC, Australia.
¹³ Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
¹⁴ Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
¹⁵ Department of Pediatrics, Peking University First Hospital, Beijing, China.
¹⁶ Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
¹⁷ Tel Aviv University Medical School, Tel Aviv, Israel.
¹⁸ Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
¹⁹ 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.
²⁰ Edmond and Lily Safra Children's Hospital, Pediatric Neurology Unit, Tel-Hashomer, Israel.
²¹ Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel.
²² The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
²³ Department of Medical Biology University of Melbourne, Melbourne, VIC, Australia.
²⁴ Service de génétique médicale, CHU Nantes, Nantes, France.
²⁵ Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
²⁶ Section for Medical Genetics, Telemark Hospital, Skien, Norway.
²⁷ Department of Neurosciences, Queensland Children's Hospital, Brisbane, QLD, Australia.
²⁸ Service de Neuropédiatrie, Pôle de Médecine et Spécialités Médicales, CHRU de Lille, Lille, France.
²⁹ Lyon University Hospitals, Departments of Genetics, Lyon, France.
³⁰ T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
³¹ University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands.
³² INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Bron, France.
³³ Child and Youth, Randers Regional Hospital, Randers, Denmark.
³⁴ Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
³⁵ Stichting Epilepsie Instellingen Nederland, Zwolle, The Netherlands.
³⁶ Clinical Hospital "Psychiatry", Kyiv, Ukraine.
³⁷ Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
³⁸ Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
³⁹ Pediatric Neurology Unit, University Hospitals, Geneva, Switzerland.
⁴⁰ Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel.
⁴¹ Medical Genetics, St George's University Hospitals NHS FT, Cranmer Tce, London, United Kingdom.
⁴² Department of Neuroscience, Pharmacology and Child Health, Children's Hospital A. Meyer and University of Florence, Florence, Italy.
⁴³ CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, France.
⁴⁴ INSERM UMR1231 GAD, FHU-TRANSLAD, Université de Bourgogne, Dijon, France.
⁴⁵ Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
⁴⁶ Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
⁴⁷ Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
⁴⁸ Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand.
⁴⁹ One Centre of Genetics, Vadodara, India.
⁵⁰ Neuropaediatric Unit, Shaare Zedek Medical Centre, Hebrew University School of Medicine, Jerusalem, Israel.
⁵¹ Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom and Chalfont Centre for Epilepsy, Bucks, UK.
⁵² Institut de Génétique Médicale, Hopital Jeanne de Flandre, Lille University Hospital, Lille, France.
⁵³ Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
⁵⁴ Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK.
⁵⁵ College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
⁵⁶ UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
⁵⁷ INSERM UMR1231 GAD, Dijon, France.
⁵⁸ Academic Center for Epileptology, Kempenhaege, Department of Neurology, Heeze, The Netherlands.
⁵⁹ School of Medicine, University of Queensland, Brisbane, QLD, Australia.
⁶⁰ Molecular Genetics Lab, Wolfson Medical Center, Holon, Israel.
⁶¹ Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA.
⁶² White Matter Disease Care, Pediatric Neurology Unit, Dana-Dwak Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
⁶³ Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.
⁶⁴ Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.
⁶⁵ Royal Children's Hospital, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.
⁶⁶ Murdoch Children's Research Institute, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.
⁶⁷ Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.
⁶⁸ Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia. i.scheffer@unimelb.edu.au.

^# Contributed equally.

PMID: 33144681
DOI: 10.1038/s41436-020-00988-9

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.

Keywords: KIAA2022; NEXMIF; developmental and epileptic encephalopathy; epilepsy; intellectual disability.

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References

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NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Affiliations

NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns

Authors

Affiliations

Abstract

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Molecular Biology Databases