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 Brilstra; Oyvind 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; Sebastien Kury; 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. Moller; Ingrid E. Scheffer

doi:10.1038/s41436-020-00988-9

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 BrilstraOyvind 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, Sebastien Kury, 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. Moller, Ingrid E. Scheffer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-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 language	English
Pages (from-to)	363-373
Number of pages	11
Journal	Genetics in Medicine
Volume	23
Issue number	2
Early online date	4 Nov 2020
DOIs	https://doi.org/10.1038/s41436-020-00988-9
Publication status	Published - Feb 2021

Keywords

NEXMIF
KIAA2022
developmental and epileptic encephalopathy
epilepsy
intellectual disability
INTELLECTUAL DISABILITY
ILAE COMMISSION
POSITION PAPER
MUTATIONS
EPILEPSY
CLASSIFICATION
INACTIVATION
MOSAICISM
MYOCLONIA

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Cite this

Stamberger, H., Hammer, T. B., Gardella, E., Vlaskamp, D. R. M., Bertelsen, B., Mandelstam, S., de Lange, I., Zhang, J., Myers, C. T., Fenger, C., Afawi, Z., Fuerte, E. P. A., Andrade, D. M., Balcik, Y., Ben Zeev, B., Bennett, M. F., Berkovic, S. F., Isidor, B., Bouman, A., ... Scheffer, I. E. (2021). NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns. Genetics in Medicine, 23(2), 363-373. https://doi.org/10.1038/s41436-020-00988-9

@article{89bb2576a2f346e4a06f0feecf08fcf9,

title = "NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns",

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 = "NEXMIF, KIAA2022, developmental and epileptic encephalopathy, epilepsy, intellectual disability, INTELLECTUAL DISABILITY, ILAE COMMISSION, POSITION PAPER, MUTATIONS, EPILEPSY, CLASSIFICATION, INACTIVATION, MOSAICISM, MYOCLONIA",

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

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{\textquoteright}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{\textquoteright}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. Publisher Copyright: {\textcopyright} 2020, American College of Medical Genetics and Genomics.",

year = "2021",

month = feb,

doi = "10.1038/s41436-020-00988-9",

language = "English",

volume = "23",

pages = "363--373",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "2",

}

Stamberger, H, Hammer, TB, Gardella, E, Vlaskamp, DRM, Bertelsen, B, Mandelstam, S, de Lange, I, Zhang, J, Myers, CT, Fenger, C, Afawi, Z, Fuerte, EPA, Andrade, DM, Balcik, Y, Ben Zeev, B, Bennett, MF, Berkovic, SF, Isidor, B, Bouman, A, Brilstra, E, Busk, OL, Cairns, A, Caumes, R, Chatron, N, Dale, RC, de Geus, C, Edery, P, Gill, D, Granild-Jensen, JB, Gunderson, L, Gunning, B, Heimer, G, Helle, JR, Hildebrand, MS, Hollingsworth, G, Kharytonov, V, Klee, EW, Koeleman, BPC, Koolen, DA, Korff, C, Kury, S, Lesca, G, Lev, D, Leventer, RJ, Mackay, MT, Macke, EL, McEntagart, M, Mohammad, SS, Monin, P, Montomoli, M, Morava, E, Moutton, S, Muir, AM, Parrini, E, Procopis, P, Ranza, E, Reed, L, Reif, PS, Rosenow, F, Rossi, M, Sadleir, LG, Sadoway, T, Schelhaas, HJ, Schneider, AL, Shah, K, Shalev, R, Sisodiya, SM, Smol, T, Stumpel, CTRM, Stuurman, K, Symonds, JD, Mau-Them, FT, Verbeek, N, Verhoeven, JS, Wallace, G, Yosovich, K, Zarate, YA, Zerem, A, Zuberi, SM, Guerrini, R, Mefford, HC, Patel, C, Zhang, Y-H, Moller, RS & Scheffer, IE 2021, 'NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns', Genetics in Medicine, vol. 23, no. 2, pp. 363-373. https://doi.org/10.1038/s41436-020-00988-9

TY - JOUR

T1 - NEXMIF encephalopathy

T2 - an X-linked disorder with male and female phenotypic patterns

AU - Stamberger, Hannah

AU - Hammer, Trine B.

AU - Gardella, Elena

AU - Vlaskamp, Danique R. M.

AU - Bertelsen, Birgitte

AU - Mandelstam, Simone

AU - de Lange, Iris

AU - Zhang, Jing

AU - Myers, Candace T.

AU - Fenger, Christina

AU - Afawi, Zaid

AU - Fuerte, Edith P. Almanza

AU - Andrade, Danielle M.

AU - Balcik, Yunus

AU - Ben Zeev, Bruria

AU - Bennett, Mark F.

AU - Berkovic, Samuel F.

AU - Isidor, Bertrand

AU - Bouman, Arjan

AU - Brilstra, Eva

AU - Busk, Oyvind L.

AU - Cairns, Anita

AU - Caumes, Roseline

AU - Chatron, Nicolas

AU - Dale, Russell C.

AU - de Geus, Christa

AU - Edery, Patrick

AU - Gill, Deepak

AU - Granild-Jensen, Jacob Bie

AU - Gunderson, Lauren

AU - Gunning, Boudewijn

AU - Heimer, Gali

AU - Helle, Johan R.

AU - Hildebrand, Michael S.

AU - Hollingsworth, Georgie

AU - Kharytonov, Volodymyr

AU - Klee, Eric W.

AU - Koeleman, Bobby P. C.

AU - Koolen, David A.

AU - Korff, Christian

AU - Kury, Sebastien

AU - Lesca, Gaetan

AU - Lev, Dorit

AU - Leventer, Richard J.

AU - Mackay, Mark T.

AU - Macke, Erica L.

AU - McEntagart, Meriel

AU - Mohammad, Shekeeb S.

AU - Monin, Pauline

AU - Montomoli, Martino

AU - Morava, Eva

AU - Moutton, Sebastien

AU - Muir, Alison M.

AU - Parrini, Elena

AU - Procopis, Peter

AU - Ranza, Emmanuelle

AU - Reed, Laura

AU - Reif, Philipp S.

AU - Rosenow, Felix

AU - Rossi, Massimiliano

AU - Sadleir, Lynette G.

AU - Sadoway, Tara

AU - Schelhaas, Helenius J.

AU - Schneider, Amy L.

AU - Shah, Krati

AU - Shalev, Ruth

AU - Sisodiya, Sanjay M.

AU - Smol, Thomas

AU - Stumpel, Connie T. R. M.

AU - Stuurman, Kyra

AU - Symonds, Joseph D.

AU - Mau-Them, Frederic Tran

AU - Verbeek, Nienke

AU - Verhoeven, Judith S.

AU - Wallace, Geoffrey

AU - Yosovich, Keren

AU - Zarate, Yuri A.

AU - Zerem, Ayelet

AU - Zuberi, Sameer M.

AU - Guerrini, Renzo

AU - Mefford, Heather C.

AU - Patel, Chirag

AU - Zhang, Yue-Hua

AU - Moller, Rikke S.

AU - Scheffer, Ingrid E.

N1 - 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. Publisher Copyright: © 2020, American College of Medical Genetics and Genomics.

PY - 2021/2

Y1 - 2021/2

N2 - 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.

AB - 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.

KW - NEXMIF

KW - KIAA2022

KW - developmental and epileptic encephalopathy

KW - epilepsy

KW - intellectual disability

KW - INTELLECTUAL DISABILITY

KW - ILAE COMMISSION

KW - POSITION PAPER

KW - MUTATIONS

KW - EPILEPSY

KW - CLASSIFICATION

KW - INACTIVATION

KW - MOSAICISM

KW - MYOCLONIA

U2 - 10.1038/s41436-020-00988-9

DO - 10.1038/s41436-020-00988-9

M3 - Article

C2 - 33144681

SN - 1098-3600

VL - 23

SP - 363

EP - 373

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 2

ER -