Phenotypic Divergence of JAG1 ‐ and NOTCH2 ‐Associated Alagille Syndrome & Disease‐Specific NOTCH2 Variant Classification Guidelines
Year: 2025
Type: article
Study design: Observational Study
Abstract: BACKGROUND & AIMS: Alagille syndrome (ALGS) is a rare, autosomal dominant disorder with high phenotypic heterogeneity. Disease-causing variants are primarily identified in Jagged1 (JAG1), with fewer reported in NOTCH2. JAG1 variants cause disease through a mechanism of haploinsufficiency, but the mechanism for NOTCH2 variants is not completely understood, making classification of variants more challenging. Using a large, international patient cohort acquired through the Global ALagille Alliance (GALA) study, we sought to improve classification of NOTCH2 variants and study phenotypic differences between NOTCH2- and JAG1-related disease. METHODS: Clinical and molecular data from 952 individuals with ALGS in GALA were analysed and disease features compared between those with JAG1 (n = 902) and NOTCH2 (n = 34) variants. Previously reported and newly identified NOTCH2 variants were reinterpreted based on disease-specific modifications to the American College of Medical Genetics and Genomics (ACMG) guidelines. The Kaplan-Meier method was utilised to assess native liver survival (NLS) and overall survival (OS) and gene comparisons were made with the log-rank test. RESULTS: Thirty NOTCH2 variants, including 18 novel variants, were identified and classified in our GALA cohort. Phenotypic analyses revealed a significantly lower incidence of characteristic facies, posterior embryotoxon, cardiac involvement and butterfly vertebrae in individuals with NOTCH2 variants compared to those with JAG1 variants (p < 0.001). No differences were identified in NLS or OS. Review of 61 previously reported NOTCH2 variants resulted in the re-classification of 19 likely pathogenic or pathogenic to VOUS (31.1%) with less than half retaining their originally published classification (34.4%; n = 21). CONCLUSIONS: We report on a large global study on NOTCH2 genetics and phenotype, which increases the number of reported NOTCH2 variants by 30%. All variants were reclassified using current guidelines, and comparison of the JAG1 and NOTCH2 cohorts demonstrates clear phenotypic divergence between these groups. These data suggest that reliance on classical clinical phenotyping may miss patients with NOTCH2-related disease and supports an inclusive approach to genetic testing.
Source: Liver International
DOI: 10.1111/liv.70251
Authors: Shannon M. Vandriel, Li‐Ting Li, Huiyu She, Jian‐She Wang, Kathleen M. Loomes, David A. Piccoli, Irena Jankowska, Piotr Czubkowski, Dorota Gliwicz‐Miedzińska, Lorenzo D'Antiga, Emanuele Nicastro, Florence Lacaille, Dominique Debray, Étienne M. Sokal, Tanguy Demaret, Rima L. Fawaz, Silvia Nastasio, Kyung Mo Kim, Seak Hee Oh, Björn Fischler, Henrik Arnell, Catherine Larson‐Nath, Winita Hardikar, Sahana Shankar, Shikha S. Sundaram, Alexander Chaidez, Pinar Bulut, Pier Luigi Calvo, Mureo Kasahara, Niviann Blondet, Eberhard Lurz, Anna‐Maria Kavallar, Emmanuel M. Gonzales, Emmanuel Jacquemin, Jérôme Bouligand, Noelle H. Ebel, Jeffrey A. Feinstein, Susan M. Siew, Michael O. Stormon, Saul J. Karpen, Rene Romero, M. Kyle Jensen, Catalina Jaramillo, James E. Squires, Sarah M. Bedoyan, Deirdre A. Kelly, Jane Hartley, Henkjan J. Verkade, Way Seah Lee, Chatmanee Lertudomphonwanit, Ryan T. Fischer, Henry C. Lin, Nathalie Rock, Yael Mozer‐Glassberg, Amin J. Roberts, Helen M. Evans, Wikrom Karnsakul, Gabriella Nebbia, Victorien M. Wolters, Pamela L. Valentino, Jesus Quintero Bernabeu, Amal A. Aqul, Cigdem Arikan, María Legarda Tamara, Cristina Molera Busoms, Thomas Damgaard Sandahl, Giuseppe Indolfi, Andréanne N. Zizzo, Aglaia Zellos, Ruben E. Quiros‐Tejeira, Ermelinda Santos‐Silva, Kathleen B. Schwarz, Jernej Brecelj, Maria Camila Sanchez, Maria Lorena Cavalieri, Christos Tzivinikos, Sabina Wiecek, John Eshun, Nanda Kerkar, Quais Mujawar, Zerrin Önal, Cristina Gonçalves, Jennifer Garcia, Seema Alam, Carolina Jimenez‐Rivera, Luis Bujanda, Richard J. Thompson, Bettina E. Hansen, Nancy B. Spinner, Melissa A. Gilbert, Binita M. Kamath, The Global ALagille Alliance (GALA) Study Group
Institutions: University of Toronto, Hospital for Sick Children, Children's Hospital of Fudan University, Children's Hospital of Philadelphia, University of Pennsylvania, Children's Memorial Health Institute, Ospedale Papa Giovanni XXIII, University of Milano-Bicocca, Hôpital Necker-Enfants Malades, Université Paris Cité, Cliniques Universitaires Saint-Luc, Yale University, Boston Children's Hospital, Harvard University, Asan Medical Center, University of Ulsan, Karolinska University Hospital, Karolinska Institutet, University of Minnesota, Royal Children's Hospital, Narayana Health, Mazumdar Shaw Medical Centre, Children's Hospital Colorado, University of Colorado Anschutz, Phoenix Children's Hospital, Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, Ospedale Regina Margherita, National Center For Child Health and Development, Seattle Children's Hospital, LMU Klinikum, Ludwig-Maximilians-Universität München, Innsbruck Medical University, Universität Innsbruck, Inserm, Université Paris-Saclay, Bicêtre Hospital, Assistance Publique – Hôpitaux de Paris, Stanford Medicine, Stanford University, Lucile Packard Children's Hospital, Children's Hospital at Westmead, Westmead Hospital, Emory University, Virginia Commonwealth University, Children's Healthcare of Atlanta, Primary Children's Hospital, University of Utah, University of Pittsburgh, Birmingham Women’s and Children’s NHS Foundation Trust, University of Birmingham, University Medical Center Groningen, University of Groningen, University of Malaya, Mahidol University, Ramathibodi Hospital, Children's Mercy Hospital, Oregon Health & Science University, University of Geneva, University Hospital of Geneva, Schneider Children's Medical Center, Starship Children's Health, Johns Hopkins University, Johns Hopkins Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University Medical Center Utrecht, Hospital Universitario La Paz, Azienda Ospedaliera San Gerardo, Vall d'Hebron Hospital Universitari, ERN TRANSPLANT-CHILD, The University of Texas Southwestern Medical Center, Koç University, Hospital de Cruces, Aarhus University Hospital, Meyer Children's Hospital, Western University, London Health Sciences Centre, Children's Hospital of Western Ontario, Mitera Hospital, University of Nebraska Medical Center, Universidade do Porto, University of California San Diego, Rady Children's Hospital-San Diego, Ljubljana University Medical Centre, Hospital Italiano de Buenos Aires, Mohammed Bin Rashid University of Medicine and Health Sciences, Medical University of Silesia, University of Tennessee Health Science Center, Le Bonheur Children's Hospital, University of Rochester Medicine, Massachusetts General Hospital, University of Rochester, University of Manitoba, Istanbul University-Cerrahpaşa, Istanbul University, ERN RARE-LIVER, University of Miami, Miami Transplant Institute, Institute of Liver and Biliary Sciences, Children's Hospital of Eastern Ontario, University of the Basque Country, Biogipuzkoa Health Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Donostiako Unibertsitate Ospitalea, King's College London, University Health Network, Toronto General Hospital
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,780
Funders: Yale University, Alexion Pharmaceuticals, Children's Hospital of Philadelphia, University of Pennsylvania, Emory University, University of Minnesota, National Center for Child Health and Development, University of Pittsburgh, Virginia Commonwealth University, Seattle Children's Research Institute, Children's Healthcare of Atlanta, Ipsen Biopharmaceuticals, Horizon Pharmaceuticals, Sarepta Therapeutics, Audentes Therapeutics, Alagille Syndrome Alliance, Institut National de la Santé et de la Recherche Médicale, National Natural Science Foundation of China, University of Ulsan, Fudan University, Karolinska Institutet, Ludwig-Maximilians-Universität München, Hospital for Sick Children, Université Paris-Saclay, Assistance publique-Hôpitaux de Paris, Medizinische Universität Innsbruck, Universität Innsbruck, Ipsen, National Institutes of Health, School of Medicine, Stanford University, School of Medicine, Emory University, Perelman School of Medicine, University of Pennsylvania, National Institute of Diabetes and Digestive and Kidney Diseases, Eunice Kennedy Shriver National Institute of Child Health and Human Development, University of Colorado School of Medicine, Anschutz Medical Campus, Cliniques Universitaires Saint-Luc
OpenAlex ID: W4412788259