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Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders.

Reza MaroofianRauan KaiyrzhanovElisa CaliMina ZamaniMaha S ZakiMatteo P FerlaDomenico TortoraSaeid SadeghianSaadia Maryam SaadiUzma AbdullahEhsan Ghayoor KarimianiStephanie EfthymiouGözde YeşilShahryar AlaviAisha M Al ShamsiHoma TajsharghiMohamed S Abdel-HamidNebal Waill SaadiFuad Al MutairiLama AlabdiChristian BeetzZafar AliMehran Beiraghi ToosiSabine Rudnik-SchönebornMeisam BabaeiPirjo IsohanniJameel MuhammadSheraz KhanMaha Al ShalanScott E HickeyDaphna MaromEmil ElhananManju A KurianDana MarafiAlihossein SaberiMohammad HamidRobert V V SpaullLinyan MengSeema LalaniShazia MaqboolFatima RahmanJürgen SeegerTimothy Blake PalculictTracy LauDavid MurphyNiccolo Emanuele MencacciKatharina SteindlAnais BegemannAnita RauchSinan AkbasAslanger Ayça DilrubaVincenzo SalpietroHammad YousafShay Ben-ShacharKatarina EjeskärAida I Al AqeelFrances A HighAmy E Armstrong-JavorsSeyed Mohammadsaleh ZahraeiTahereh SeifiJawaher ZeighamiGholamreza ShariatiAlireza SedaghatSamaneh Noroozi AslMohmmad ShahrooeiGiovanni ZifarelliLydie BurglenClaudia RavelliJohannes ZschockeUlrich A SchatzMaryam GhavideldarestaniWalaa A KamelHilde Van EschAnnette HackenbergJenny C TaylorLihadh Al-GazaliPeter BauerJoseph J GleesonFowzan Sami AlkurayaJames R LupskiHamid GalehdariReza AzizimalamiriWendy K ChungShahid Mahmood BaigHenry HouldenMariasavina Severino
Published in: Brain : a journal of neurology (2023)
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. Utilizing exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up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-dyskinestic encephalopathy to variable neurodevelopmental disorder with movement abnormalities. It is characterised 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".
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