EBioMedicine (Sep 2024)
Clinical and neuroradiological spectrum of biallelic variants in NOTCH3Research in context
- Pablo Iruzubieta,
- César Augusto Pinheiro Ferreira Alves,
- Aisha M. Al Shamsi,
- Gehad ElGhazali,
- Maha S. Zaki,
- Lorenzo Pinelli,
- Diego Lopergolo,
- Bernard P.H. Cho,
- Amy A. Jolly,
- Amna Al Futaisi,
- Fatema Al-Amrani,
- Jessica Galli,
- Elisa Fazzi,
- Katarina Vulin,
- Francisco Barajas-Olmos,
- Holger Hengel,
- Bayan Mohammed Aljamal,
- Vahideh Nasr,
- Farhad Assarzadegan,
- Michele Ragno,
- Luigi Trojano,
- Naomi Meave Ojeda,
- Arman Çakar,
- Silvia Bianchi,
- Francesca Pescini,
- Anna Poggesi,
- Amal Al Tenalji,
- Majid Aziz,
- Rahema Mohammad,
- Aziza Chedrawi,
- Nicola De Stefano,
- Giovanni Zifarelli,
- Ludger Schöls,
- Tobias B. Haack,
- Adriana Rebelo,
- Stephan Zuchner,
- Filiz Koc,
- Lyn R. Griffiths,
- Lorena Orozco,
- Karla García Helmes,
- Meisam Babaei,
- Peter Bauer,
- Won Chan Jeong,
- Ehsan Ghayoor Karimiani,
- Miriam Schmidts,
- Joseph G. Gleeson,
- Wendy K. Chung,
- Fowzan Sami Alkuraya,
- Bita Shalbafan,
- Hugh S. Markus,
- Henry Houlden,
- Reza Maroofian
Affiliations
- Pablo Iruzubieta
- Department of Neurogenetics, UCL Institute of Neurology London Queen Square and National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom; Department of Neurology, Donostia University Hospital, Biogipuzkoa Health Research Institute, Donostia-San Sebastián, Spain; CIBERNED, Centro de Investigación Biomédica en Red en Enfermedades Neurodegenerativas-Instituto de Salud Carlos III (CIBER-CIBERNED-ISCIII), 28029, Madrid, Spain
- César Augusto Pinheiro Ferreira Alves
- Neuroradiology Division, Department of Radiology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Division of Neuroradiology, Department of Radiology, Children's Hospital of Philadelphia, 3401 Civic Center Blvd., Philadelphia, PA, 19104, USA
- Aisha M. Al Shamsi
- Genetic Division, Paediatrics Department, Tawam Hospital, Al-Ain, United Arab Emirates
- Gehad ElGhazali
- Sheikh Khalifa Medical City, Purelab, Purehealth, Abu Dhabi, United Arab Emirates; College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
- Maha S. Zaki
- Clinical Genetics Department, Human Genetics and Genome Research Institute, National Research Centre, El-Tahrir Street, Dokki, Cairo, Egypt
- Lorenzo Pinelli
- Neuroradiology Unit, Pediatric Neuroradiology Section, ASST SpedaliCivili, Brescia, Italy
- Diego Lopergolo
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
- Bernard P.H. Cho
- Department of Clinical Neurosciences, University of Cambridge, United Kingdom
- Amy A. Jolly
- Department of Clinical Neurosciences, University of Cambridge, United Kingdom
- Amna Al Futaisi
- Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University, Oman
- Fatema Al-Amrani
- Department of Child Health, College of Medicine and Health Sciences, Sultan Qaboos University, Oman
- Jessica Galli
- Child Neurology and Psychiatry Unit, ASST SpedaliCivili of Brescia, Brescia, Italy; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
- Elisa Fazzi
- Child Neurology and Psychiatry Unit, ASST SpedaliCivili of Brescia, Brescia, Italy; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy
- Katarina Vulin
- Department of Medical and Laboratory Genetics, ERN-Ithaca Zagreb Center, Children's Hospital Zagreb, Zagreb, Croatia; Centre of Excellence for Reproductive and Regenerative Medicine, Medical School University of Zagreb, Zagreb, Croatia
- Francisco Barajas-Olmos
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
- Holger Hengel
- Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany
- Bayan Mohammed Aljamal
- Department of Translational Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
- Vahideh Nasr
- Department of Neurology - Kermanshah Imam Reza (AS) Hospital Complex, Kermanshah University of Medical Sciences, Kermanshah, Iran
- Farhad Assarzadegan
- Department of Neurology, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences(SBUMS), Tehran, Iran
- Michele Ragno
- Pianeta Salute, Viale Assisi, 88, 63084, Villa Pigna, Ascoli Piceno, Italy
- Luigi Trojano
- Department of Psychology, University of Campania ‘Luigi Vanvitelli’, Viale Ellittico 31, 81100, Caserta, Italy
- Naomi Meave Ojeda
- Rady Children's Institute for Genomic Medicine, University of California, San Diego, La Jolla, USA
- Arman Çakar
- Neuromuscular Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, 34093, Istanbul, Turkey
- Silvia Bianchi
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
- Francesca Pescini
- Department of Emergency, Stroke Unit, Careggi University Hospital, Florence, Italy; Department of NEUROFARBA, University of Florence, Florence, Italy
- Anna Poggesi
- Department of Emergency, Stroke Unit, Careggi University Hospital, Florence, Italy; Department of NEUROFARBA, University of Florence, Florence, Italy
- Amal Al Tenalji
- Sheikh Khalifa Medical City, Purelab, Purehealth, Abu Dhabi, United Arab Emirates
- Majid Aziz
- Sheikh Khalifa Medical City, Department of Pediatric Neurology, Abu Dhabi, United Arab Emirates
- Rahema Mohammad
- Department of Neurogenetics, UCL Institute of Neurology London Queen Square and National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom
- Aziza Chedrawi
- Department of Neurosciences, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
- Nicola De Stefano
- Department of Medicine, Surgery and Neurosciences, University of Siena, Siena, Italy; UOC Neurologia e Malattie Neurometaboliche, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
- Giovanni Zifarelli
- CENTOGENE GmbH, Am Strande 7, 18055, Rostock, Germany
- Ludger Schöls
- Department of Neurology and Hertie-Institute for Clinical Brain Research, University of Tübingen, 72076, Tübingen, Germany; German Center of Neurodegenerative Diseases (DZNE), 72076, Tübingen, Germany
- Tobias B. Haack
- Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
- Adriana Rebelo
- Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
- Stephan Zuchner
- Dr. John T. Macdonald Foundation Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
- Filiz Koc
- Department of Neurology, Faculty of Medicine, Cukurova University, Adana, Turkey
- Lyn R. Griffiths
- Genomics Research Centre, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Queensland University of Technology, 60 Musk Ave, Kelvin Grove, QLD, 4059, Australia
- Lorena Orozco
- Immunogenomics and Metabolic Diseases Laboratory, Instituto Nacional de Medicina Genómica, SS, CDMX, Mexico
- Karla García Helmes
- Department of Genetics, General Hospital - Dr. Aurelio Valdivieso, Oaxaca de Juárez, Oaxaca, Mexico
- Meisam Babaei
- Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran
- Peter Bauer
- CENTOGENE GmbH, Am Strande 7, 18055, Rostock, Germany
- Won Chan Jeong
- 3billion, Seoul, South Korea
- Ehsan Ghayoor Karimiani
- Genetics Section, Molecular and Clinical Sciences Research Institute, St. George's, University of London, London, United Kingdom
- Miriam Schmidts
- Pediatrics Genetics Division, Center for Pediatrics and Adolescent Medicine, Faculty of Medicine, Freiburg University, Mathildenstrasse 1, 79106, Freiburg, Germany; CIBSS-Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
- Joseph G. Gleeson
- Rady Children's Institute for Genomic Medicine, University of California, San Diego, La Jolla, USA
- Wendy K. Chung
- Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, USA
- Fowzan Sami Alkuraya
- Department of Translational Genomics, Centre for Genomic Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia
- Bita Shalbafan
- Cellular and Molecular Endocrine Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Hugh S. Markus
- Department of Clinical Neurosciences, University of Cambridge, United Kingdom
- Henry Houlden
- Department of Neurogenetics, UCL Institute of Neurology London Queen Square and National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom
- Reza Maroofian
- Department of Neurogenetics, UCL Institute of Neurology London Queen Square and National Hospital for Neurology and Neurosurgery, University College London, London, United Kingdom; Corresponding author.
- Journal volume & issue
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Vol. 107
p. 105297
Abstract
Summary: Background: NOTCH3 encodes a transmembrane receptor critical for vascular smooth muscle cell function. NOTCH3 variants are the leading cause of hereditary cerebral small vessel disease (SVD). While monoallelic cysteine-involving missense variants in NOTCH3 are well-studied in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), patients with biallelic variants in NOTCH3 are extremely rare and not well characterised. Methods: In this study, we present clinical and genetic data from 25 patients with biallelic NOTCH3 variants and conduct a literature review of another 25 cases (50 patients in total). Brain magnetic resonance imaging (MRI) were analysed by expert neuroradiologists to better understand the phenotype associated with biallelic NOTCH3 variants. Findings: Our systematic analyses verified distinct genotype-phenotype correlations for the two types of biallelic variants in NOTCH3. Biallelic loss-of-function variants (26 patients) lead to a neurodevelopmental disorder characterised by spasticity, childhood-onset stroke, and periatrial white matter volume loss resembling periventricular leukomalacia. Conversely, patients with biallelic cysteine-involving missense variants (24 patients) fall within CADASIL spectrum phenotype with early adulthood onset stroke, dementia, and deep white matter lesions without significant volume loss. White matter lesion volume is comparable between patients with biallelic cysteine-involving missense variants and individuals with CADASIL. Notably, monoallelic carriers of loss-of-function variants are predominantly asymptomatic, with only a few cases reporting nonspecific headaches. Interpretation: We propose a NOTCH3-SVD classification depending on dosage and variant type. This study not only expands our knowledge of biallelic NOTCH3 variants but also provides valuable insight into the underlying mechanisms of the disease, contributing to a more comprehensive understanding of NOTCH3-related SVD. Funding: The Wellcome Trust, the MRC.
