Biallelic MED27 variants lead to variable ponto-cerebello-lental degeneration with movement disorders
Authors: Maroofian Reza , Kaiyrzhanov Rauan , Cali Elisa , Zamani Mina , Zaki Maha S , Ferla Matteo , Tortora Domenico , Sadeghian Saeid , Saadi Saadia Maryam , Abdullah Uzma , Karimiani Ehsan Ghayoor , Efthymiou Stephanie , Yeşil Gözde , Alavi Shahryar , Al Shamsi Aisha M , Tajsharghi Homa , Abdel-Hamid Mohamed S , Saadi Nebal Waill , Al Mutairi Fuad , Alabdi Lama , Beetz Christian , Ali Zafar , Toosi Mehran Beiraghi , Rudnik-Schöneborn Sabine , Babaei Meisam , Isohanni Pirjo , Muhammad Jameel , Khan Sheraz , Al Shalan Maha , Hickey Scott E , Marom Daphna , Elhanan Emil , Kurian Manju A , Marafi Dana , Saberi Alihossein , Hamid Mohammad , Spaull Robert , Meng Linyan , Lalani Seema , Maqbool Shazia , Rahman Fatima , Seeger Jürgen , Palculict Timothy Blake , Lau Tracy , Murphy David , Mencacci Niccolo Emanuele , Steindl Katharina , Begemann Anais , Rauch Anita , Akbas Sinan , Aslanger Ayça Dilruba , Salpietro Vincenzo , Yousaf Hammad , Ben-Shachar Shay , Ejeskär Katarina , Al Aqeel Aida I , High Frances A , Armstrong-Javors Amy E , Zahraei Seyed Mohammadsaleh , Seifi Tahereh , Zeighami Jawaher , Shariati Gholamreza , Sedaghat Alireza , Asl Samaneh Noroozi , Shahrooei Mohmmad , Zifarelli Giovanni , Burglen Lydie , Ravelli Claudia , Zschocke Johannes , Schatz Ulrich A , Ghavideldarestani Maryam , Kamel Walaa A , Van Esch Hilde , Hackenberg Annette , Taylor Jenny C , Al-Gazali Lihadh , Bauer Peter , Gleeson Joseph J , Alkuraya Fowzan Sami , Lupski James R , Galehdari Hamid , Azizimalamiri Reza , Chung Wendy K , Baig Shahid Mahmood , Houlden Henry , Severino Mariasavina 
Published: July 2023

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Using exome sequencing and extensive international genetic data sharing, 39 unpublished affected individuals from 18 independent families with biallelic missense variants in MED27 have been identified (29 females, mean age at last follow-up 17 ±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