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

H Stamberger, TB Hammer, E Gardella, DRM Vlaskamp, B Bertelsen, S Mandelstam, I Lange, J Zhang, CT Myers, C Fenger, Z Afawi, EP Almanza Fuerte, DM Andrade, Y Balcik, B Ben Zeev, MF Bennett, SF Berkovic, B Isidor, Arjan Bouman, E BrilstraØL Busk, A Cairns, R Caumes, N Chatron, RC Dale, C de Geus, P Edery, D Gill, JB Granild-Jensen, L Gunderson, B Gunning, G Heimer, JR Helle, MS Hildebrand, G Hollingsworth, V Kharytonov, EW Klee, BPC Koeleman, DA (David) Koolen, C Korff, S Küry, G Lesca, D Lev, RJ Leventer, MT Mackay, EL Macke, M McEntagart, SS Mohammad, P Monin, M Montomoli, E Morava, S Moutton, AM Muir, E Parrini, P Procopis, E Ranza, L Reed, PS Reif, F Rosenow, M Rossi, LG Sadleir, T Sadoway, HJ Schelhaas, AL Schneider, K Shah, R Shalev, SM Sisodiya, T Smol, Ctrm Stumpel, Kyra Stuurman, JD Symonds, FT Mau-Them, N Verbeek, JS Verhoeven, G Wallace, K Yosovich, YA Zarate, A Zerem, SM Zuberi, R Guerrini, HC Mefford, C Patel, YH Zhang, RS Møller, IE Scheffer

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32 Citations (Scopus)


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
Pages (from-to)363-373
Number of pages11
JournalGenetics in Medicine
Issue number2
Publication statusPublished - 1 Feb 2021

Bibliographical note

Funding Information:
R.G. has acted as an investigator for studies with Zogenix, Biocodex, Biomarin, UCB, Angelini, and Eisai Inc. He has been a speaker and on advisory boards for Zogenix, Biocodex, Novartis, Biomarin, GW Pharma, and Biocodex; serves/has served on the editorial boards of Epilepsia, Progress in Epileptic Disorders, Neuropediatrics, Journal of Child Neurology, Seizure, BMC Medical Genetics, Topics in Epilepsy, and Neurology. He receives/has received research support from the Italian Ministry of Health, The European Community, The Tuscany Region, the Mariani Foundation, The Pisa Foundation, The Fund of Epilepsy, The GKT Special Trustees, The Italian Federation for Epilepsy, and The Italian Association for Epilepsy. I.E.S. serves/has served on the editorial boards of the Annals of Neurology, Neurology, and Epileptic Disorders; may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics, Inc., and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/ 001321 (TECH ID:2012-009) with royalties paid. She has served on scientific advisory boards for UCB, Eisai, GlaxoSmithKline, BioMarin, Nutricia, Rogcon, and Xenon Pharmaceuticals; has received speaker honoraria from GlaxoSmithKline, UCB, Bio-Marin, Biocodex, and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, and Eisai; has served as an investigator for Zogenix, Zynerba, Ultragenyx, GW Pharma, UCB, Eisai, Anavex Life Scienand Marinus; and has consulted for Zynerba Pharmaceuticals, Atheneum Partners, Ovid Therapeutics, and UCB. She receives/has received research support from the National Health and Medical Research Council of Australia, Health Research Council of New Zealand, CURE, Australian Epilepsy Research Fund, March of Dimes and NIH/NINDS. D.M.A. has consulted for Eisai, UCB, and is part of the MAB of Stoke Therapeutics and DSF. B.G. has received consultancy fees from GW Pharmaceuticals companies, Zogenix, and Ovid/Takeda; and is a principal investigator for GW Research Ltd, Zogenix, LivaNova, Marinus Pharmaceuticals, and UCB. L.G.S. reports grants from Health Research Council of New Zealand, grants from Cure Kids New Zealand, during the conduct of the study; grants and personal fees from Zynerba, other from Sequirus, other from Nutricia, outside the submitted work. S.M.Z. has received research funding from Epilepsy Research UK, UCB Pharma, Glasgow Children’s Hospital Charity, Dravet Syndrome UK. He serves as Editor-in-Chief of European Journal of Pediatric Neurology for which he receives an honorarium from Elsevier Ltd. He has participated in educational symposia/advisory boards/ consulted for GW Pharma, Zogenix Ltd, Biocodex, Nutricia, and Encoded Genomics. The other authors declare no conflicts of interest.

Funding Information:
We thank the patients and their families for participating in our research. We further want to acknowledge the Epi25 Consortium for providing a platform for exome sequencing for epilepsy patients that led to a diagnosis for some of the patients included in this study. H.S. was PhD fellow of the Fund for Scientific Research Flanders (1125416N). H.C.M. received support from the National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS) (R01NS069605). D.M.A. received funding from EpLink, of the Ontario Brain Institute for array comparative genomic hybridization (aCGH) analysis. This study was supported by the Key Research Project of the Ministry of Science and Technology of China (2016YFC0904400 and 2016YFC0904401; through J.Z. and Y.A.Z.), Cure Kids New Zealand (through L.G.S.) and the Victorian Government’s Operational Infrastructure Support Program and the Australian Government National Health and Medical Research Council (NHMRC) Independent Medical Research Institutes Infrastructure Support Scheme (IRIISS) (through M.B.). The work was generated within ITHACA (Intellectual disability, TeleHealth, And Congenital Anomalies), European Reference Network on Rare Congenital Malformations, and Rare Intellectual Disability.

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© 2020, American College of Medical Genetics and Genomics.

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