Biallelic <i>MED27</i> variants lead to variable ponto-cerebello-lental degeneration with movement disorders-Reference-Cited by-同舟云学术

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

Published:2023-07-30 Issue:12 Volume:146 Page:5031-5043
ISSN:0006-8950
Container-title:Brain
language:en
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Author:

Maroofian Reza¹^ORCID,Kaiyrzhanov Rauan¹^ORCID,Cali Elisa¹,Zamani Mina²³⁴^ORCID,Zaki Maha S⁵,Ferla Matteo⁶^ORCID,Tortora Domenico⁷^ORCID,Sadeghian Saeid⁸^ORCID,Saadi Saadia Maryam⁹,Abdullah Uzma¹⁰,Karimiani Ehsan Ghayoor¹¹¹²¹³,Efthymiou Stephanie¹^ORCID,Yeşil Gözde¹⁴,Alavi Shahryar¹,Al Shamsi Aisha M¹⁵,Tajsharghi Homa¹⁶,Abdel-Hamid Mohamed S¹⁷,Saadi Nebal Waill¹⁸¹⁹,Al Mutairi Fuad²⁰²¹,Alabdi Lama²²²³,Beetz Christian²⁴,Ali Zafar²⁵²⁶,Toosi Mehran Beiraghi²⁷,Rudnik-Schöneborn Sabine²⁸^ORCID,Babaei Meisam²⁹,Isohanni Pirjo³⁰³¹^ORCID,Muhammad Jameel⁹³²,Khan Sheraz⁹^ORCID,Al Shalan Maha²⁰,Hickey Scott E³³³⁴,Marom Daphna³⁵,Elhanan Emil³⁶,Kurian Manju A³⁷³⁸,Marafi Dana³⁹⁴⁰^ORCID,Saberi Alihossein³⁴¹,Hamid Mohammad⁴²^ORCID,Spaull Robert³⁶³⁷^ORCID,Meng Linyan³⁸,Lalani Seema³⁸,Maqbool Shazia⁴³,Rahman Fatima⁴³,Seeger Jürgen⁴⁴^ORCID,Palculict Timothy Blake⁴⁵,Lau Tracy¹,Murphy David¹,Mencacci Niccolo Emanuele⁴⁶,Steindl Katharina⁴⁷,Begemann Anais⁴⁷,Rauch Anita⁴⁷^ORCID,Akbas Sinan¹⁴,Aslanger Ayça Dilruba¹⁴^ORCID,Salpietro Vincenzo¹⁴⁸,Yousaf Hammad⁹,Ben-Shachar Shay⁴⁹⁵⁰,Ejeskär Katarina¹⁶,Al Aqeel Aida I⁵¹⁵²⁵³,High Frances A⁵⁴⁵⁵,Armstrong-Javors Amy E⁵⁵⁵⁶,Zahraei Seyed Mohammadsaleh²,Seifi Tahereh²³,Zeighami Jawaher³⁴,Shariati Gholamreza³⁴¹,Sedaghat Alireza³⁵⁷,Asl Samaneh Noroozi⁵⁸,Shahrooei Mohmmad⁵⁹⁶⁰,Zifarelli Giovanni²⁴,Burglen Lydie⁶¹⁶²,Ravelli Claudia⁶³,Zschocke Johannes²⁸,Schatz Ulrich A²⁸⁶⁴,Ghavideldarestani Maryam⁶⁵,Kamel Walaa A⁴⁶⁶⁶,Van Esch Hilde⁶⁷⁶⁸,Hackenberg Annette⁶⁹,Taylor Jenny C⁶,Al-Gazali Lihadh⁷⁰,Bauer Peter²⁴,Gleeson Joseph J⁷¹⁷²,Alkuraya Fowzan Sami⁷³^ORCID,Lupski James R³⁹⁷⁴⁷⁵,Galehdari Hamid²⁴,Azizimalamiri Reza⁸,Chung Wendy K⁷⁶,Baig Shahid Mahmood⁹⁷⁷,Houlden Henry¹^ORCID,Severino Mariasavina⁷^ORCID

Affiliation:

1. Department of Neuromuscular Diseases, University College London, Queen Square, Institute of Neurology , London WC1N 3BG , UK

2. Department of Biology, Faculty of Science, Shahid Chamran University of Ahvaz , Ahvaz , Iran

3. Narges Medical Genetics and Prenatal Diagnosis Laboratory , Kianpars, Ahvaz , Iran

4. Ati Mehr Kasra Genetics Institute , Kianpars, Ahvaz , Iran

5. Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre , Cairo 12622 , Egypt

6. Wellcome Centre for Human Genetics, University of Oxford and Oxford NIHR Biomedical Research Centre , Oxford, OX3 7BN UK

7. Neuroradiology Unit, IRCCS Istituto Giannina Gaslini , 16147 Genoa , Italy

8. Department of Pediatric Neurology, Golestan Medical, Educational, and Research Center, Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran

9. Human Molecular Genetics Laboratory, Health Biotechnology Division, National Institute for Biotechnology and Genetic Engineering (NIBGE) College, PIEAS , 44000 Faisalabad , Pakistan

10. University Institute of Biochemistry and Biotechnology, PMAS Arid Agriculture University , 46300 Rawalpindi , Pakistan

11. Department of Medical Genetics, Next Generation Genetic Polyclinic , Mashhad , Iran

12. Molecular and Clinical Sciences Institute, St. George’s, University of London , London SW17 0RE , UK

13. Innovative Medical Research Center, Mashhad Branch, Islamic Azad University , Mashhad , Iran

14. Department of Medical Genetics, Istanbul Faculty of Medicine, Istanbul University , 34093 Istanbul , Turkey

15. Genetic Division, Pediatrics Department, Tawam Hospital , Al Ain , UAE

16. School of Health Science, Division Biomedicine and Translational Medicine, University of Skovde , SE-541 28 Skovde , Sweden

17. Medical Molecular Genetics Department, Human Genetics and Genome Research Institute, National Research Centre , 12622 Cairo , Egypt

18. College of Medicine, University of Baghdad , 10071 Baghdad , Iraq

19. Children Welfare Teaching Hospital , 10071 Baghdad , Iraq

20. Genetics and Precision Medicine department, King Abdullah Specialized Children’s Hospital, King Abdulaziz Medical City, Ministry of National Guard Health Affairs , 22384 Riyadh , Saudi Arabia

21. King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs , 22384 Riyadh , Saudi Arabia

22. Department of Zoology, College of Science, King Saud University , 11421 Riyadh , Saudi Arabia

23. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center , 12713 Riyadh , Saudi Arabia

24. Centogene GmbH , 18055 Rostock , Germany

25. Department of Cellular and Molecular Medicine, WJC PANUM, University of Copenhagen , DK-1165 Copenhagen , Denmark

26. Centre for Biotechnology and Microbiology, University of Swat , Swat 19120 , Pakistan

27. Pediatric Neurology Department Pediatric Ward Faculty of Medicine, Mashhad University of Medical Sciences , Mashhad , Iran

28. Institute of Human Genetics, Medical University Innsbruck , 6020 Innsbruck , Austria

29. Department of Pediatrics, North Khorasan University of Medical Sciences , Bojnurd , Iran

30. Research Programs Unit, Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki , 00014 Helsinki , Finland

31. Department of Child Neurology, Children’s Hospital, Paediatric Research Center, University of Helsinki and Helsinki University Hospital , 00014 Helsinki , Finland

32. Centre for Regenerative Medicine and Stem Cell Research, Juma Building, Aga Khan University , Karachi 74800 , Pakistan

33. Division of Genetic & Genomic Medicine, Nationwide Children’s Hospital, Columbus , OH 43205 , USA

34. Department of Pediatrics, The Ohio State University College of Medicine, Columbus , OH 43210 , USA

35. Genetics Institute and Genomic Center, Tel Aviv Sourasky Medical Center, and Faculty of Medicine, Tel Aviv University , Tel-Aviv , Israel

36. Nephro-Genetic Clinic, Nephrology Department and Genetics Institute, Tel Aviv Medical Center , Tel Aviv 64239 , Israel

37. Molecular Neurosciences, Developmental Neurosciences, Zayed Centre for Research into Rare Disease in Children, UCL Great Ormond Street Institute of Child Health , London WC1N 1EH , UK

38. Department of Neurology, Great Ormond Street Hospital , London WC1N 1EH , UK

39. Department of Molecular and Human Genetics, Baylor College of Medicine , Houston, TX 77030 , USA

40. Department of Pediatrics, Faculty of Medicine, Kuwait University , Safat 13110 , Kuwait

41. Department of Medical Genetics, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran

42. Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran , Tehran , Iran

43. Developmental-Behavioural Paediatrics Department, University of Child Health Sciences & The Children’s Hospital , 54000 Lahore , Pakistan

44. Center for Social Pediatrics and Epilepsy Outpatient Clinic Frankfurt Mitte , 60316 Frankfurt am Main , Germany

45. GeneDx , Gaithersburg, MD 20877 , USA

46. Department of Neurology, Feinberg School of Medicine, Northwestern University , Chicago, IL 60611 , USA

47. Institute of Medical Genetics, University of Zurich , 8952 Schlieren , Switzerland

48. Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L’Aquila , 67100 L’Aquila , Italy

49. Clalit Research Institute, Clalit Health Services , 6578898 Ramat Gan , Israel

50. Faculty of Medicine, Tel Aviv University , Tel Aviv , Israel

51. Department of Pediatrics, Prince Sultan Military Medical City , 12233 Riyadh , Saudi Arabia

52. American University of Beirut , 1107 2020 Beirut , Lebanon

53. Alfaisal University , 11533 Riyadh , Saudi Arabia

54. Division of Medical Genetics, Massachusetts General Hospital , Boston, MA 02114 , USA

55. Harvard Medical School , Boston, MA 02115 , USA

56. Department of Pediatric Neurology, Massachusetts General Hospital , Boston, MA 02114 , USA

57. Diabetes Research center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences , Ahvaz , Iran

58. Department of Pediatrics Endocrinology, Mashhad University of Medical Sciences , Mashhad , Iran

59. Specialized Immunology Laboratory of Dr Shahrooei, Sina Medical Complex , Ahvaz , Iran

60. Department of Microbiology and Immunology, Clinical and Diagnostic Immunology, KU Leuven , 3000 Leuven , Belgium

61. Cerebellar Malformations and Congenital diseases Reference Center and Neurogenetics Lab, Department of Genetics, Armand Trousseau Hospital, AP-HP Sorbonne Université , 75006 Paris , France

62. Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR 1163 , 75015 Paris , France

63. Pediatric Neurology Department, Movement Disorders Center, Armand Trousseau Hospital, AP-HP Sorbonne Université , 75006 Paris , France

64. Institute of Human Genetics, Klinikum rechts der Isar, Technische Universität Munich , 81675 Munich , Germany

65. Hull York Medical School , Hull HU6 7RX , UK

66. Department of Neurology, Faculty of Medicine, Beni-Suef University , 62521 Beni Suef , Egypt

67. Center for Human Genetics, University Hospitals Leuven , 3000 Leuven , Belgium

68. Laboratory for the Genetics of Cognition, Department of Human Genetics, KU Leuven–University of Leuven , 3000 Leuven , Belgium

69. Department of Pediatric Neurology, University Children's Hospital Zürich, University of Zürich , 8032 Zürich , Switzerland

70. Departments of Pediatrics, College of Medicine and Health Sciences, United Arab Emirates University , Al Ain , UAE

71. Department of Neurosciences, University of California , San Diego, La Jolla, CA 92093 , USA

72. Rady Children’s Institute for Genomic Medicine , San Diego, CA 92025 , USA

73. Department of Translational Genomics, Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center , Riyadh 11211 , Saudi Arabia

74. Texas Children’s Hospital , Houston, TX 77030 , USA

75. Human Genome Sequencing Center, Baylor College of Medicine , Houston, TX 77030 , USA

76. Boston Children’s Hospital and Harvard Medical School Boston , MA 02115 , USA

77. Department of Biological and Biomedical Sciences, Aga Khan University , 74800 Karachi , Pakistan

Abstract

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’.

Funder

Health Innovation Challenge Fund

European Academy of Neurology

Rosetrees

Trust

National Institute for Neurological Disorders and Stroke

Baylor College of Medicine-GREGoR Program

Seventh Framework Programme

National Institute for Health Research

Sir Jules Thorn Charitable Trust Award

Rosetrees Trust

Wellcome Trust