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

Reza Maroofian*, Rauan Kaiyrzhanov, Elisa Cali, Mina Zamani, Maha S. Zaki, Matteo Ferla, Domenico Tortora, Saeid Sadeghian, Saadia Maryam Saadi, Uzma Abdullah, Ehsan Ghayoor Karimiani, Stephanie Efthymiou, Gözde Yeşil, Shahryar Alavi, Aisha M. Al Shamsi, Homa Tajsharghi, Mohamed S. Abdel-Hamid, Nebal Waill Saadi, Fuad Al Mutairi, Lama AlabdiChristian Beetz, Zafar Ali, Mehran Beiraghi Toosi, Sabine Rudnik-Schöneborn, Meisam Babaei, Pirjo Isohanni, Jameel Muhammad, Sheraz Khan, Maha Al Shalan, Scott E. Hickey, Daphna Marom, Emil Elhanan, Manju A. Kurian, Dana Marafi, Alihossein Saberi, Mohammad Hamid, Robert Spaull, Linyan Meng, Seema Lalani, Shazia Maqbool, Fatima Rahman, Jürgen Seeger, Timothy Blake Palculict, Tracy Lau, David Murphy, Niccolo Emanuele Mencacci, Katharina Steindl, Anais Begemann, Anita Rauch, Sinan Akbas, Ayça Dilruba Aslanger, Vincenzo Salpietro, Hammad Yousaf, Shay Ben-Shachar, Katarina Ejeskär, Aida I. Al Aqeel, Frances A. High, Amy E. Armstrong-Javors, Seyed Mohammadsaleh Zahraei, Tahereh Seifi, Jawaher Zeighami, Gholamreza Shariati, Alireza Sedaghat, Samaneh Noroozi Asl, Mohmmad Shahrooei, Giovanni Zifarelli, Lydie Burglen, Claudia Ravelli, Johannes Zschocke, Ulrich A. Schatz, Maryam Ghavideldarestani, Walaa A. Kamel, Hilde Van Esch, Annette Hackenberg, Jenny C. Taylor, Lihadh Al-Gazali, Peter Bauer, Joseph J. Gleeson, Fowzan Sami Alkuraya, James R. Lupski, Hamid Galehdari, Reza Azizimalamiri, Wendy K. Chung, Shahid Mahmood Baig, Henry Houlden, Mariasavina Severino*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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 Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ±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'.

Original languageEnglish
Pages (from-to)5031-5043
Number of pages13
Issue number12
StatePublished - 1 Dec 2023


FundersFunder number
Baylor College of Medicine-GREGoR Program
Health Innovation Challenge FundHICF-1009-003
National Human Genome Research InstituteU01 HG001758
National Institute of Neurological Disorders and StrokeR35 NS105078
Wellcome TrustWT104033AIA, WT093205MA
Seventh Framework Programme2012-305121, 608473
Medical Research Council
National Institute for Health and Care Research
Sir Jules Thorn Charitable Trust
Rosetrees TrustPhD2022\100042
Lastentautien Tutkimussäätiö
European Academy of Neurology
UCLH Biomedical Research Centre203141/Z/16/Z


    • cerebellar atrophy
    • cerebello-lental degeneration
    • dystonia
    • gene transcription
    • mediator complex
    • neurodevelopmental disorders


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