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

6533b85bfe1ef96bd12bb651

RESEARCH PRODUCT

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

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

subject

Male Pediatrics medicine.medical_specialty INTELLECTUAL DISABILITY Autism Spectrum Disorder Encephalopathy Nerve Tissue Proteins ILAE COMMISSION MOSAICISM Epilepsy/genetics CLASSIFICATION Epilepsy Brain Diseases/genetics Genes X-Linked Seizures Intellectual disability Genotype medicine Humans developmental and epileptic encephalopathy MYOCLONIA Atonic seizure Genetics (clinical)Brain Diseases ddc:618 Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7]KIAA2022 business.industry MUTATIONS medicine.disease Phenotype Autism Spectrum Disorder/genetics Genes X-Linked/genetics Autism spectrum disorder intellectual disability NEXMIF Autism epilepsy Female INACTIVATION Human medicine Seizures/genetics business POSITION PAPER

description

Contains fulltext : 231688.pdf (Publisher’s version ) (Closed access) 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.

year	journal	country	edition	language
2021-02-01	Genetics in Medicine

10.1038/s41436-020-00988-9 https://doi.org/10.1038/s41436-020-00988-9