NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns,Genetics in Medicine

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NEXMIF encephalopathy: an X-linked disorder with male and female phenotypic patterns
Genetics in Medicine ( IF 6.6 ) Pub Date : 2020-11-04 , DOI: 10.1038/s41436-020-00988-9
Hannah Stamberger _{1,

2} , Trine B Hammer _{3,

4} , Elena Gardella _{3,

5} , Danique R M Vlaskamp _{1,

6,

7} , Birgitte Bertelsen ₈ , Simone Mandelstam _{9,

10,

11,

12,

13} , Iris de Lange ₁₄ , Jing Zhang ₁₅ , Candace T Myers ₁₆ , Christina Fenger ₃ , Zaid Afawi ₁₇ , Edith P Almanza Fuerte ₁₆ , Danielle M Andrade ₁₈ , Yunus Balcik ₁₉ , Bruria Ben Zeev _{20,

21} , Mark F Bennett _{1,

22,

23} , Samuel F Berkovic ₁ , Bertrand Isidor ₂₄ , Arjan Bouman ₂₅ , Eva Brilstra ₁₄ , Øyvind L Busk ₂₆ , Anita Cairns ₂₇ , Roseline Caumes ₂₈ , Nicolas Chatron ₂₉ , Russell C Dale ₃₀ , Christa de Geus ₃₁ , Patrick Edery _{29,

32} , Deepak Gill ₃₀ , Jacob Bie Granild-Jensen ₃₃ , Lauren Gunderson ₃₄ , Boudewijn Gunning ₃₅ , Gali Heimer _{20,

21} , Johan R Helle ₂₆ , Michael S Hildebrand _{1,

10} , Georgie Hollingsworth ₁ , Volodymyr Kharytonov ₃₆ , Eric W Klee _{34,

37} , Bobby P C Koeleman ₁₄ , David A Koolen ₃₈ , Christian Korff ₃₉ , Sébastien Küry ₂₄ , Gaetan Lesca ₂₉ , Dorit Lev _{21,

40} , Richard J Leventer _{9,

10,

11} , Mark T Mackay _{9,

10,

11} , Erica L Macke ₃₇ , Meriel McEntagart ₄₁ , Shekeeb S Mohammad ₃₀ , Pauline Monin ₂₉ , Martino Montomoli ₄₂ , Eva Morava _{34,

37} , Sebastien Moutton _{43,

44} , Alison M Muir ₁₆ , Elena Parrini ₄₂ , Peter Procopis _{30,

45} , Emmanuelle Ranza ₄₆ , Laura Reed ₄₇ , Philipp S Reif ₁₉ , Felix Rosenow ₁₉ , Massimiliano Rossi _{29,

32} , Lynette G Sadleir ₄₈ , Tara Sadoway ₁₈ , Helenius J Schelhaas ₃₅ , Amy L Schneider ₁ , Krati Shah ₄₉ , Ruth Shalev ₅₀ , Sanjay M Sisodiya ₅₁ , Thomas Smol ₅₂ , Connie T R M Stumpel ₅₃ , Kyra Stuurman ₂₅ , Joseph D Symonds _{54,

55} , Frederic Tran Mau-Them _{56,

57} , Nienke Verbeek ₁₄ , Judith S Verhoeven ₅₈ , Geoffrey Wallace _{27,

59} , Keren Yosovich ₆₀ , Yuri A Zarate ₆₁ , Ayelet Zerem _{21,

62} , Sameer M Zuberi _{54,

55} , Renzo Guerrini ₄₂ , Heather C Mefford ₁₆ , Chirag Patel ₆₃ , Yue-Hua Zhang ₁₅ , Rikke S Møller _{3,

5} , Ingrid E Scheffer _{1,

9,

10,

11,

13}

Affiliation

Epilepsy Research Centre, Department of Medicine, Austin Health, University of Melbourne, Melbourne, VIC, Australia.
Applied and Translational Neurogenomics group, Center for Molecular Neurology, VIB, and Department of Neurology, University Hospital of Antwerp, University of Antwerp, Antwerpen, Belgium.
Department of Epilepsy Genetics, Danish Epilepsy Centre Filadelfia, Dianalund, Denmark.
Clinical Genetic Department, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Institute for Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
University of Groningen, University Medical Center Groningen, Department of Neurology, Groningen, the Netherlands.
University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, The Netherlands.
Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Royal Children's Hospital, Melbourne, VIC, Australia.
Murdoch Children's Research Institute, Melbourne, VIC, Australia.
Department of Pediatrics, University of Melbourne, Melbourne, VIC, Australia.
Department of Radiology, University of Melbourne, Melbourne, VIC, Australia.
Florey Institute of Neuroscience and Mental Health, Melbourne, VIC, Australia.
Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Pediatrics, Peking University First Hospital, Beijing, China.
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA, USA.
Tel Aviv University Medical School, Tel Aviv, Israel.
Division of Neurology, Toronto Western Hospital, University of Toronto, Toronto, ON, Canada.
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.
Edmond and Lily Safra Children's Hospital, Pediatric Neurology Unit, Tel-Hashomer, Israel.
Tel Aviv University, Sackler School of Medicine, Tel Aviv, Israel.
The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC, Australia.
Department of Medical Biology University of Melbourne, Melbourne, VIC, Australia.
Service de génétique médicale, CHU Nantes, Nantes, France.
Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
Section for Medical Genetics, Telemark Hospital, Skien, Norway.
Department of Neurosciences, Queensland Children's Hospital, Brisbane, QLD, Australia.
Service de Neuropédiatrie, Pôle de Médecine et Spécialités Médicales, CHRU de Lille, Lille, France.
Lyon University Hospitals, Departments of Genetics, Lyon, France.
T.Y. Nelson Department of Neurology and Neurosurgery, The Children's Hospital at Westmead, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.
University Medical Centre Groningen, Department of Genetics, Groningen, The Netherlands.
INSERM U1028, CNRS UMR5292, Centre de Recherche en Neurosciences de Lyon, GENDEV Team, Bron, France.
Child and Youth, Randers Regional Hospital, Randers, Denmark.
Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA.
Stichting Epilepsie Instellingen Nederland, Zwolle, The Netherlands.
Clinical Hospital "Psychiatry", Kyiv, Ukraine.
Center for Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands.
Pediatric Neurology Unit, University Hospitals, Geneva, Switzerland.
Institute of Medical Genetics, Wolfson Medical Center, Holon, Israel.
Medical Genetics, St George's University Hospitals NHS FT, Cranmer Tce, London, United Kingdom.
Department of Neuroscience, Pharmacology and Child Health, Children's Hospital A. Meyer and University of Florence, Florence, Italy.
CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, France.
INSERM UMR1231 GAD, FHU-TRANSLAD, Université de Bourgogne, Dijon, France.
Discipline of Child and Adolescent Health, Sydney Medical School, University of Sydney, Sydney, NSW, Australia.
Medigenome, Swiss Institute of Genomic Medicine, Geneva, Switzerland.
Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Department of Paediatrics and Child Health, University of Otago Wellington, Wellington, New Zealand.
One Centre of Genetics, Vadodara, India.
Neuropaediatric Unit, Shaare Zedek Medical Centre, Hebrew University School of Medicine, Jerusalem, Israel.
Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, United Kingdom and Chalfont Centre for Epilepsy, Bucks, UK.
Institut de Génétique Médicale, Hopital Jeanne de Flandre, Lille University Hospital, Lille, France.
Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
Paediatric Neurosciences Research Group, Royal Hospital for Children, Glasgow, UK.
College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
UF Innovation en diagnostic genomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
INSERM UMR1231 GAD, Dijon, France.
Academic Center for Epileptology, Kempenhaege, Department of Neurology, Heeze, The Netherlands.
School of Medicine, University of Queensland, Brisbane, QLD, Australia.
Molecular Genetics Lab, Wolfson Medical Center, Holon, Israel.
Section of Genetics and Metabolism, Department of Pediatrics, University of Arkansas for Medical Sciences, Arkansas Children's Hospital, Little Rock, AR, USA.
White Matter Disease Care, Pediatric Neurology Unit, Dana-Dwak Children's Hospital, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia.

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.

中文翻译：

NEXMIF 脑病：一种具有男性和女性表型模式的 X 连锁疾病

目的

X连锁基因NEXMIF（以前的KIAA2022）的致病变异与智力障碍（ID）、自闭症谱系障碍和癫痫有关。我们旨在描绘NEXMIF脑病的女性和男性表型谱。

方法

通过国际合作，我们分析了 87名 NEXMIF脑病患者的表型和基因型。

结果

研究了 63 名女性和 24 名男性（46 名新患者）患有NEXMIF脑病，有 30 种新变体。表型特征包括 86/87 (99%) 的发育迟缓/ID、71/86 (83%) 的癫痫发作和多种合并症。以全身性癫痫发作为主，包括肌阵挛发作和失神发作（均为 46/70，66%）、眼睑肌阵挛失神（17/70，24%）和失张力发作（30/70，43%）。男性有更严重的发育障碍；女性癫痫发作的频率更高，并且从未受影响到严重受影响不等。所有NEXMIF致病变异导致过早终止密码子或有害的结构变异。大多数是从头出现的，尽管两性都发生了 X 连锁的隔离。体细胞嵌合体发生在两名男性和一个疑似父母嵌合体的家庭中。