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Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders
Department of Neuromuscular Diseases, University College London, Institute of Neurology, United Kingdom.
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translationell medicin TRIM, Translational Medicine TRIM)ORCID iD: 0000-0001-8854-5213
University of Skövde, School of Health Sciences. University of Skövde, Digital Health Research (DHEAR). (Translationell medicin TRIM, Translational Medicine TRIM)ORCID iD: 0000-0001-8962-0860
Neuroradiology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Number of Authors: 862023 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 146, no 12, p. 5031-5043Article in journal (Refereed) Published
Abstract [en]

MED27 is a subunit of the Mediator multiprotein complex, which is involved in transcriptional regulation. Biallelic MED27 variants have recently been suggested to be responsible for an autosomal recessive neurodevelopmental disorder with spasticity, cataracts and cerebellar hypoplasia. We further delineate the clinical phenotype of MED27-related disease by characterizing the clinical and radiological features of 57 affected individuals from 30 unrelated families with biallelic MED27 variants. Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ± 12.4 years, range 0.1-45). Follow-up and hitherto unreported clinical features were obtained from the published 12 families. Brain MRI scans from 34 cases were reviewed. MED27-related disease manifests as a broad phenotypic continuum ranging from developmental and epileptic-dyskinetic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterized by mild to profound global developmental delay/intellectual disability (100%), bilateral cataracts (89%), infantile hypotonia (74%), microcephaly (62%), gait ataxia (63%), dystonia (61%), variably combined with epilepsy (50%), limb spasticity (51%), facial dysmorphism (38%) and death before reaching adulthood (16%). Brain MRI revealed cerebellar atrophy (100%), white matter volume loss (76.4%), pontine hypoplasia (47.2%) and basal ganglia atrophy with signal alterations (44.4%). Previously unreported 39 affected individuals had seven homozygous pathogenic missense MED27 variants, five of which were recurrent. An emerging genotype-phenotype correlation was observed. This study provides a comprehensive clinical-radiological description of MED27-related disease, establishes genotype-phenotype and clinical-radiological correlations and suggests a differential diagnosis with syndromes of cerebello-lental neurodegeneration and other subtypes of 'neuro-MEDopathies'. 

Place, publisher, year, edition, pages
2023. Vol. 146, no 12, p. 5031-5043
Keywords [en]
cerebellar atrophy, cerebello-lental degeneration, dystonia, gene transcription, mediator complex, neurodevelopmental disorders, Adolescent, Adult, Atrophy, Cataract, Cerebellum, Child, Child, Preschool, Epilepsy, Epilepsy, Generalized, Female, Humans, Infant, Middle Aged, Movement Disorders, Phenotype, Young Adult, MED27 protein, human, diagnostic imaging, generalized epilepsy, genetics, human, mental disease, motor dysfunction, pathology, preschool child
National Category
Medical Genetics Neurology Pediatrics
Research subject
Translational Medicine TRIM
Identifiers
URN: urn:nbn:se:his:diva-23471DOI: 10.1093/brain/awad257ISI: 001106767600001PubMedID: 37517035Scopus ID: 2-s2.0-85178648913OAI: oai:DiVA.org:his-23471DiVA, id: diva2:1819517
Funder
EU, FP7, Seventh Framework Programme, 608473Wellcome trust, WT093205MAWellcome trust, WT104033AIAEU, FP7, Seventh Framework Programme, 2012-305121Wellcome trust, 203141/Z/16/Z
Note

CC BY 4.0 DEED

© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.

Correspondence to: Mariasavina Severino Neuroradiology Unit, IRCCS Istituto Giannina Gaslini Via Gerolamo Gaslini 5, 16147 Genova, GE, Italy E-mail: mariasavinaseverino@gaslini.org

Correspondence may also be addressed to: Reza Maroofian Department of Neuromuscular Diseases, University College London Queen Square Institute of Neurology Queen Square, London WC1N 3BG, UK E-mail: r.maroofian@ucl.ac.uk

Part of this research was possible thanks to the Deciphering Developmental Disorders (DDD) study. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). R.K. was supported by the European Academy of Neurology Research Training Fellowship and Rosetrees Trust PhD Plus award (PhD2022\100042). J.R.L. was supported by the National Institute for Neurological Disorders and Stroke Research Program Award R35 NS105078 and the Baylor College of Medicine-GREGoR Program (NHGRI U01 HG001758). H.T. was supported by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 608473. M.A.K. and R.S. were supported by a National Institute for Health Research professorship, Sir Jules Thorn Charitable Trust Award for Biomedical Research and the Rosetrees Trust. This study was also supported by the Wellcome Trust (WT093205MA and WT104033AIA), the Medical Research Council (H.H.), European Union’s Seventh Framework Programme (FP7/2007-2013, under grant agreement no. 2012-305121), the National Institute for Health Research (NIHR), University College London Hospitals (UCLH) and UCLH Biomedical Research Centre (BRC). For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. The NIHR Oxford Biomedical Research Centre Programme and a Wellcome Trust Core Award (203141/Z/16/Z). P.I. was supported by Foundation for Pediatric Research.

Available from: 2023-12-14 Created: 2023-12-14 Last updated: 2023-12-28Bibliographically approved

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Tajsharghi, HomaEjeskär, Katarina

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