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

Hannah Stamberger, Trine B. Hammer, Elena Gardella, Danique R.M. Vlaskamp, Birgitte Bertelsen, Simone Mandelstam, Iris de Lange, Jing Zhang, Candace T. Myers, Christina Fenger, Zaid Afawi, Edith P. Almanza Fuerte, Danielle M. Andrade, Yunus Balcik, Bruria Ben Zeev, Mark F. Bennett, Samuel F. Berkovic, Bertrand Isidor, Arjan Bouman, Eva BrilstraØyvind L. Busk, Anita Cairns, Roseline Caumes, Nicolas Chatron, Russell C. Dale, Christa de Geus, Patrick Edery, Deepak Gill, Jacob Bie Granild-Jensen, Lauren Gunderson, Boudewijn Gunning, Gali Heimer, Johan R. Helle, Michael S. Hildebrand, Georgie Hollingsworth, Volodymyr Kharytonov, Eric W. Klee, Bobby P.C. Koeleman, David A. Koolen, Christian Korff, Sébastien Küry, Gaetan Lesca, Dorit Lev, Richard J. Leventer, Mark T. Mackay, Erica L. Macke, Meriel McEntagart, Shekeeb S. Mohammad, Pauline Monin, Martino Montomoli, Eva Morava, Sebastien Moutton, Alison M. Muir, Elena Parrini, Peter Procopis, Emmanuelle Ranza, Laura Reed, Philipp S. Reif, Felix Rosenow, Massimiliano Rossi, Lynette G. Sadleir, Tara Sadoway, Helenius J. Schelhaas, Amy L. Schneider, Krati Shah, Ruth Shalev, Sanjay M. Sisodiya, Thomas Smol, Connie T.R.M. Stumpel, Kyra Stuurman, Joseph D. Symonds, Frederic Tran Mau-Them, Nienke Verbeek, Judith S. Verhoeven, Geoffrey Wallace, Keren Yosovich, Yuri A. Zarate, Ayelet Zerem, Sameer M. Zuberi, Renzo Guerrini, Heather C. Mefford, Chirag Patel, Yue Hua Zhang, Rikke S. Møller, Ingrid E. Scheffer*

*Corresponding author for this work

Research output: Contribution to journalJournal articleResearchpeer-review

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.

Original languageEnglish
JournalGenetics in Medicine
Volume23
Issue number2
Pages (from-to)363-373
ISSN1098-3600
DOIs
Publication statusPublished - Feb 2021

Keywords

  • developmental and epileptic encephalopathy
  • epilepsy
  • intellectual disability
  • KIAA2022
  • NEXMIF

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