Phenotypic Divergence of JAG1 ‐ and NOTCH2 ‐Associated Alagille Syndrome & Disease‐Specific NOTCH2 Variant Classification Guidelines
作者：Shannon M. Vandriel, Liting 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 Sokal, Tanguy Demaret, Rima 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, Pınar Bulut, Pier Luigi Calvo, Mureo Kasahara, Niviann Blondet, Eberhard Lurz, Anna‐Maria Kavallar, Emmanuel Gonzalès, Emmanuel Jacquemin, Jérôme Bouligand, Noelle H. Ebel, Jeffrey A. Feinstein, Susan Siew, Michael Stormon, Saul J. Karpen, René Romero, M. Kyle Jensen, Catalina Jaramillo, James E. Squires, Sarah M. Bedoyan, Déirdre 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 Evans, Wikrom Karnsakul, Gabriella Nebbia, Victorien M. Wolters, Pamela L. Valentino, Jesus Quintero Bernabeu, Amal Aqul, Çiğdem Arıkan, María Legarda Tamara, Cristina Molera Busoms, Thomas Damgaard Sandahl, Giuseppe Indolfi, Andréanne N. Zizzo, Aglaia Zellos, Rubén E. Quirós‐Tejeira, Ermelinda Santos Silva, Kathleen B. Schwarz, Jernej Brecelj, María Camila Sanchez, Maria Lorena Cavalieri, Christos Tzivinikos, Sabina Więcek, John Eshun, Nanda Kerkar, Quais Mujawar, Zerrin Önal, Cristina Gonçalves, Jennifer García, Seema Alam, Carolina Jiménez‐Rivera, Luís Bujanda, Richard J. Thompson, Bettina E. Hansen, Nancy B. Spinner, Melissa A. Gilbert, Binita M. Kamath, The Global ALagille Alliance (GALA) Study Group · 发表于：Liver International · 年份：2025 · DOI：10.1111/liv.70251 · 被引用次数：4 · 研究领域：Pediatric Hepatobiliary Diseases and Treatments、Gallbladder and Bile Duct Disorders、Esophageal and GI Pathology
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 wit...