Biallelic <i>MED27</i> variants lead to variable ponto-cerebello-lental degeneration with movement disorders
Reza Maroofian, Rauan Kaiyrzhanov, Elisa Calì, Mina Zamani, Maha S. Zaki, Matteo P. Ferla, Domenico Tortora, Saeid Sadeghian, Saadia Maryam Saadi, Uzma Abdullah, Ehsan Ghayoor Karimiani, Stéphanie Efthymiou, Gözde Yeşil, Shahryar Alavi, Aisha M. Al Shamsi, Homa Tajsharghi, Mohamed S. Abdel‐Hamid, Nebal Waill Saadi, Fuad Al Mutairi, Lama AlAbdi, Christian 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 R. Lalani, Shazia Maqbool, Fatima Rahman, Jürgen Seeger, Timothy Blake Palculict, Tracy Lau, David Murphy, Niccolò E. Mencacci, Katharina Steindl, Anaïs Begemann, Anita Rauch, Sinan Akbaş, Ayça Dilruba Aslanger, Vincenzo Salpietro, Hammad Yousaf, Shay Ben‐Shachar, Katarina Ejeskär, Aida I. Al Aqeel, Frances A. High, Amy Armstrong‐Javors, Seyed Mohammadsaleh Zahraei, Tahereh Seifi, Jawaher Zeighami, Gholamreza Shariati, Alireza Sedaghat, Samaneh Noroozi Asl, Mohmmad Shahrooei, Giovanni Zifarelli, Lydie Bürglen, 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 S. Alkuraya, James R. Lupski, Hamid Galehdari, Reza Azizi Malamiri, Wendy K. Chung, Shahid Mahmood Baig, Henry Houlden, Mariasavina Severino
Abstract
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 Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ±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'.