학술논문
Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.
Document Type
Academic Journal
Author
Faqeih EA; Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.; Alghamdi MA; Medical Genetics Division, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Medical Genetic Division, Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia.; Almahroos MA; Section of Medical Genetics, Children's Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.; Alharby E; Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.; Almuntashri M; Department of Radiology, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.; Alshangiti AM; Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.; Clément P; Department of Medical Genetics and Mitovasc INSERM 1083, CNRS 6015, Angers University Hospital, Angers, France.; Calame DG; Division of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.; Qebibo L; Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique, AP-HP, Sorbonne Université, Hôpital Trousseau, 75012, Paris, France.; Burglen L; Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique, AP-HP, Sorbonne Université, Hôpital Trousseau, 75012, Paris, France; Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR, 1163, F-75015, Paris, France.; Doco-Fenzy M; CHU Reims, SFR CAP Sante, EA3801, Reims, France and CHU de Nantes, service de génétique médicale, Nantes, France.; Mastrangelo M; Child Neurology and Psychiatry Unit, Department of Human Neuroscience, Sapienza-University of Rome, Rome, Italy.; Torella A; Department of Precision Medicine, Università della Campania 'Luigi Vanvitelli' ,Naples, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.; Manti F; Child Neurology and Psychiatry Unit, Department of Human Neuroscience, Sapienza-University of Rome, Rome, Italy.; Nigro V; Department of Precision Medicine, Università della Campania 'Luigi Vanvitelli' ,Naples, Italy; Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy.; Alban Z; Department of Medical Genetics and Mitovasc INSERM 1083, CNRS 6015, Angers University Hospital, Angers, France.; Alharbi GS; Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.; Hashmi JA; Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.; Alraddadi R; Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.; Alamri R; Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia.; Mitani T; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.; Magalie B; Department of Medical Genetics and Mitovasc INSERM 1083, CNRS 6015, Angers University Hospital, Angers, France.; Coban-Akdemir Z; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.; Geckinli BB; Center of Genetics Diagnosis, Zeynep Kamil Maternity and Children's Training and Research Hospital, Istanbul, Turkey; Department of Medical Genetics, School of Medicine, Marmara University, Istanbul, Turkey.; Pehlivan D; Division of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX; Texas Children's Hospital, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.; Romito A; Medical Reporting & Genomic Research, CENTOGENE GmbH, Rostock, Germany.; Karageorgou V; Medical Reporting & Genomic Research, CENTOGENE GmbH, Rostock, Germany.; Martini J; Medical Reporting & Genomic Research, CENTOGENE GmbH, Rostock, Germany.; Colin E; Department of Medical Genetics and Mitovasc INSERM 1083, CNRS 6015, Angers University Hospital, Angers, France.; Bonneau D; Department of Medical Genetics and Mitovasc INSERM 1083, CNRS 6015, Angers University Hospital, Angers, France.; Bertoli-Avella A; Medical Reporting & Genomic Research, CENTOGENE GmbH, Rostock, Germany.; Lupski JR; Texas Children's Hospital, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; Department of Pediatrics, Baylor College of Medicine, Houston, TX.; Pastore A; Dementia Research Institute at King's College London, The Wohl Institute, 5 Cutcome Rd, London SE59RT, UK.; Peake RWA; Department of Laboratory Medicine, Boston Children's Hospital, Boston, MA.; Dallol A; Noor Diagnostics and Discovery, Innovation Cluster, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.; Alfadhel M; King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia; Genetics and Precision Medicine Department, King Abdullah Specialized Children Hospital (KASCH), King Abdulaziz Medical City (KAMC), Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.; Almontashiri NAM; Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia; College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia. Electronic address: nmontashri@taibahu.edu.sa.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 9815831 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1530-0366 (Electronic) Linking ISSN: 10983600 NLM ISO Abbreviation: Genet Med Subsets: MEDLINE
Subject
Language
English
Abstract
Purpose: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified.
Methods: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes.
Results: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect.
Conclusion: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.
Competing Interests: Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center, and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. J.R.L. serves on the Scientific Advisory Board of Baylor Genetics. Baylor College of Medicine and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics, which performs clinical microarray analysis and other genomic studies (exome sequencing, genome sequencing) for patient and family care. N.A.M.A. is a paid consultant for Noor Diagnostics and Discovery, which performs genetic and genomic studies (exome sequencing, genome sequencing) for patient and family care. All other authors declare no conflicts of interest.
(Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Methods: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes.
Results: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect.
Conclusion: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.
Competing Interests: Conflict of Interest J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Genetics Center, and is a coinventor on multiple US and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, genomic disorders, and bacterial genomic fingerprinting. J.R.L. serves on the Scientific Advisory Board of Baylor Genetics. Baylor College of Medicine and Miraca Holdings have formed a joint venture with shared ownership and governance of Baylor Genetics, which performs clinical microarray analysis and other genomic studies (exome sequencing, genome sequencing) for patient and family care. N.A.M.A. is a paid consultant for Noor Diagnostics and Discovery, which performs genetic and genomic studies (exome sequencing, genome sequencing) for patient and family care. All other authors declare no conflicts of interest.
(Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)