Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines

Shannon M Vandriel¹, Li-Ting Li², Huiyu She², Jian-She Wang², Kathleen M Loomes³, David A Piccoli³, Irena Jankowska⁴, Piotr Czubkowski⁴, Dorota Gliwicz-Miedzińska⁴, Lorenzo D'Antiga^{5

6}, Emanuele Nicastro⁵, Florence Lacaille⁷, Dominique Debray⁸, Étienne M Sokal⁹, Tanguy Demaret⁹, Rima L Fawaz¹⁰, Silvia Nastasio¹¹, Kyung Mo Kim¹², Seak Hee Oh¹², Björn Fischler^{13

14}, Henrik Arnell^{13

15}, Catherine Larson-Nath¹⁶, Winita Hardikar¹⁷, Sahana Shankar¹⁸, Shikha S Sundaram¹⁹, Alexander Chaidez¹⁹, Pinar Bulut²⁰, Pier Luigi Calvo²¹, Mureo Kasahara²², Niviann Blondet²³, Eberhard Lurz²⁴, Anna-Maria Kavallar²⁵, Emmanuel M Gonzales^{26

27}, Emmanuel Jacquemin^{26

27}, Jérôme Bouligand²⁸, Noelle H Ebel²⁹, Jeffrey A Feinstein³⁰, Susan M Siew³¹, Michael O Stormon³¹, Saul J Karpen^{32

33}, Rene Romero³², M Kyle Jensen³⁴, Catalina Jaramillo³⁴, James E Squires³⁵, Sarah M Bedoyan³⁵, Deirdre A Kelly³⁶, Jane Hartley³⁶, Henkjan J Verkade³⁷, Way Seah Lee³⁸, Chatmanee Lertudomphonwanit³⁹, Ryan T Fischer⁴⁰, Henry C Lin⁴¹, Nathalie Rock⁴², Yael Mozer-Glassberg⁴³, Amin J Roberts⁴⁴, Helen M Evans⁴⁴, Wikrom Karnsakul⁴⁵, Gabriella Nebbia⁴⁶, Victorien M Wolters⁴⁷, Pamela L Valentino²³, Jesus Quintero Bernabeu^{48

49

50}, Amal A Aqul⁵¹, Cigdem Arikan⁵², María Legarda Tamara⁵³, Cristina Molera Busoms⁵⁴, Thomas Damgaard Sandahl⁵⁵, Giuseppe Indolfi⁵⁶, Andréanne N Zizzo⁵⁷, Aglaia Zellos⁵⁸, Ruben E Quiros-Tejeira⁵⁹, Ermelinda Santos-Silva^{60

61}, Kathleen B Schwarz⁶², Jernej Brecelj^{63

64}, Maria Camila Sanchez⁶⁵, Maria Lorena Cavalieri⁶⁵, Christos Tzivinikos⁶⁶, Sabina Wiecek⁶⁷, John Eshun⁶⁸, Nanda Kerkar^{69

70}, Quais Mujawar⁷¹, Zerrin Önal⁷², Cristina Gonçalves^{73

74}, Jennifer Garcia⁷⁵, Seema Alam⁷⁶, Carolina Jimenez-Rivera⁷⁷, Luis Bujanda⁷⁸, Richard J Thompson⁷⁹, Bettina E Hansen^{80

81}, Nancy B Spinner⁸², Melissa A Gilbert⁸², Binita M Kamath^{1

3}; Global ALagille Alliance (GALA) Study Group

Affiliations

¹ Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Canada.
² The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.
³ Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁴ Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
⁵ Pediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
⁶ Department of Medicine and Surgery, University of Milano - Bicocca, Milan, Italy.
⁷ Pediatric Gastroenterology-Nutrition and Hepatology Units, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
⁸ Pediatric Liver Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, ERN RARE LIVER, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
⁹ Service de Gastroentérologie & Hépatologie Pédiatrique, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
¹⁰ Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
¹¹ Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹² Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
¹³ Department of Paediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
¹⁴ CLINTEC, Karolinska Institutet, ERN Rare Liver, Stockholm, Sweden.
¹⁵ Department of Women's and Children's Health, Karolinska Institutet, ERN Rare Liver, Stockholm, Sweden.
¹⁶ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁷ Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Australia.
¹⁸ Mazumdar Shaw Medical Center, Narayana Health, Bangalore, India.
¹⁹ Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA.
²⁰ Division of Pediatric Gastroenterology and Hepatology, Phoenix Children's Hospital, Phoenix, Arizona, USA.
²¹ Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza, Turin, Italy.
²² Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.
²³ Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, Washington, USA.
²⁴ Department of Pediatrics, LMU Munich, Dr. von Hauner Children's Hospital, University Hospital, Munich, Germany.
²⁵ Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
²⁶ Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Rare Pediatric Liver Diseases, FILFOIE, ERN RARE LIVER, Bicêtre Hospital, AP-HP, University of Paris-Saclay, Le Kremlin-Bicêtre, France.
²⁷ Inserm U1193, Hepatinov, University of Paris-Saclay, Orsay, France.
²⁸ Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire de Bicêtre, Hôpitaux Universitaires Paris-Saclay, Le Kremlin-Bicêtre, France.
²⁹ Division of Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, USA.
³⁰ Department of Pediatrics (Cardiology), Lucile Packard Children's Hospital, Stanford University School of Medicine, Palo Alto, California, USA.
³¹ Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, Australia.
³² Division of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Healthcare of Atlanta & Emory University School of Medicine, Atlanta, Georgia, USA.
³³ Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University, Richmond, Virginia, USA.
³⁴ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.
³⁵ Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
³⁶ Liver Unit, Birmingham Women's & Children's Hospital NHS Trust, University of Birmingham, Birmingham, UK.
³⁷ Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
³⁸ Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
³⁹ Division of Gastroenterology, Department of Pediatrics, Ramathibodi Hospital Mahidol University, Bangkok, Thailand.
⁴⁰ Section of Hepatology, Department of Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri, USA.
⁴¹ Division of Pediatric Gastroenterology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA.
⁴² Division of Pediatric Specialties, Department of Pediatrics, Gynecology, and Obstetrics, Swiss Pediatric Liver Center, University Hospitals Geneva, University of Geneva, Geneva, Switzerland.
⁴³ Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel.
⁴⁴ Department of Paediatric Gastroenterology, Starship Child Health, Auckland, New Zealand.
⁴⁵ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁴⁶ Servizio di Epatologia Pediatrica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁴⁷ Department of Pediatric Gastroenterology, University Medical Centre Utrecht, Utrecht, the Netherlands.
⁴⁸ Pediatric Hepatology and Liver Transplant Department, Hospital Universiatri Vall d'Hebron, Barcelona, Spain.
⁴⁹ European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori Hospital, Monza, Italy.
⁵⁰ European Reference Network on Transplantation in Children (ERN-TransplantChild), La Paz Institute of Biomedical Research, Hospital Universitario La Paz, Madrid, Spain.
⁵¹ University of Texas Southwestern Medical Centre in Dallas and Children's Health, Dallas, Texas, USA.
⁵² Department of Pediatric Gastroenterology and Organ Transplant, Koc University School of Medicine, Istanbul, Turkey.
⁵³ Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain.
⁵⁴ Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
⁵⁵ Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
⁵⁶ Meyer Children's Hospital IRCCS, Florence, Italy.
⁵⁷ Division of Paediatric Gastroenterology and Hepatology, London Health Sciences Centre, Children's Hospital, Western University, London, Ontario, Canada.
⁵⁸ Mitera Children's Hospital, Athens, Greece.
⁵⁹ Department of Pediatrics, Children's Nebraska and University of Nebraska Medical Center, Omaha, Nebraska, USA.
⁶⁰ Centro Materno-Infantil do Norte Albino Aroso, Centro Hospitalar Universitário de Santo António, Porto, Portugal.
⁶¹ UCIBIO - Applied Molecular Biosciences Unit, Biochemistry Laboratory, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
⁶² Division of Pediatric Gastroenterology, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California, USA.
⁶³ Pediatric Gastroenterology, Hepatology and Nutrition, University Medical Center Ljubljana, Ljubljana, Slovenia.
⁶⁴ Department of Pediatrics, Faculty of Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia.
⁶⁵ Pediatric Gastroenterology and Hepatology Division, Hospital Italiano Buenos Aires, Buenos Aires, Argentina.
⁶⁶ Department of Paediatric Gastroenterology, Al Jalila Children's Specialty Hospital, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE.
⁶⁷ Department of Pediatrics, Medical University of Silesia in Katowice, Katowice, Poland.
⁶⁸ Department of Pediatric Gastroenterology, The University of Tennessee Health Science Center, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
⁶⁹ Massachusetts General Hospital for Children, Boston, Massachusetts, USA.
⁷⁰ University of Rochester Medical Center, Rochester, New York, USA.
⁷¹ Section of Pediatric Gastroenterology, Department of Pediatrics, University of Manitoba, Winnipeg, Canada.
⁷² Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey.
⁷³ European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Lisbon, Portugal.
⁷⁴ Pediatric Gastroenterology/Hepatology Center, Lisbon, Portugal.
⁷⁵ Division of Pediatric Gastroenterology, Hepatology and Nutrition/Miami Transplant Institute, University of Miami, Miami, Florida, USA.
⁷⁶ Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
⁷⁷ Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁷⁸ Department of Hepatology and Gastroenterology, Biodonostia Health Research Institute - Donostia University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain.
⁷⁹ Institute of Liver Studies, King's College London, London, UK.
⁸⁰ Toronto General Hospital University Health Network, Toronto, Canada.
⁸¹ Institute of Health Policy, Management and Evaluation, Toronto, Canada.
⁸² Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

PMID: 40742203
PMCID: PMC12312628
DOI: 10.1111/liv.70251

Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines

Shannon M Vandriel et al. Liver Int. 2025 Sep.

. 2025 Sep;45(9):e70251.

doi: 10.1111/liv.70251.

Authors

Affiliations

¹ Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children and the University of Toronto, Toronto, Canada.
² The Center for Pediatric Liver Diseases, Children's Hospital of Fudan University, Shanghai, China.
³ Division of Gastroenterology, Hepatology and Nutrition, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁴ Department of Gastroenterology, Hepatology, Nutrition Disturbances and Pediatrics, The Children's Memorial Health Institute, Warsaw, Poland.
⁵ Pediatric Hepatology, Gastroenterology and Transplantation, Ospedale Papa Giovanni XXIII, Bergamo, Italy.
⁶ Department of Medicine and Surgery, University of Milano - Bicocca, Milan, Italy.
⁷ Pediatric Gastroenterology-Nutrition and Hepatology Units, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
⁸ Pediatric Liver Unit, National Reference Centre for Rare Pediatric Liver Diseases (Biliary Atresia and Genetic Cholestasis), FILFOIE, ERN RARE LIVER, Necker-Enfants Malades Hospital, University of Paris, Paris, France.
⁹ Service de Gastroentérologie & Hépatologie Pédiatrique, Cliniques Universitaires Saint-Luc, Brussels, Belgium.
¹⁰ Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut, USA.
¹¹ Division of Gastroenterology, Hepatology, & Nutrition, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹² Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Republic of Korea.
¹³ Department of Paediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
¹⁴ CLINTEC, Karolinska Institutet, ERN Rare Liver, Stockholm, Sweden.
¹⁵ Department of Women's and Children's Health, Karolinska Institutet, ERN Rare Liver, Stockholm, Sweden.
¹⁶ Division of Pediatric Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis, Minnesota, USA.
¹⁷ Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Melbourne, Australia.
¹⁸ Mazumdar Shaw Medical Center, Narayana Health, Bangalore, India.
¹⁹ Section of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics and the Digestive Health Institute, Children's Hospital of Colorado, University of Colorado School of Medicine, Aurora, Colorado, USA.
²⁰ Division of Pediatric Gastroenterology and Hepatology, Phoenix Children's Hospital, Phoenix, Arizona, USA.
²¹ Pediatric Gastroenterology Unit, Regina Margherita Children's Hospital, Azienda Ospedaliera-Universitaria Citta' della Salute e della Scienza, Turin, Italy.
²² Organ Transplantation Center, National Center for Child Health and Development, Tokyo, Japan.
²³ Gastroenterology and Hepatology, Seattle Children's Hospital, Seattle, Washington, USA.
²⁴ Department of Pediatrics, LMU Munich, Dr. von Hauner Children's Hospital, University Hospital, Munich, Germany.
²⁵ Department of Paediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
²⁶ Pediatric Hepatology and Liver Transplantation Unit, National Reference Centre for Rare Pediatric Liver Diseases, FILFOIE, ERN RARE LIVER, Bicêtre Hospital, AP-HP, University of Paris-Saclay, Le Kremlin-Bicêtre, France.
²⁷ Inserm U1193, Hepatinov, University of Paris-Saclay, Orsay, France.
²⁸ Service de Génétique Moléculaire, Pharmacogénétique et Hormonologie, Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire de Bicêtre, Hôpitaux Universitaires Paris-Saclay, Le Kremlin-Bicêtre, France.
²⁹ Division of Gastroenterology, Department of Pediatrics, Stanford University School of Medicine, Palo Alto, California, USA.
³⁰ Department of Pediatrics (Cardiology), Lucile Packard Children's Hospital, Stanford University School of Medicine, Palo Alto, California, USA.
³¹ Department of Gastroenterology, The Children's Hospital at Westmead, Sydney, Australia.
³² Division of Pediatric Gastroenterology, Hepatology & Nutrition, Children's Healthcare of Atlanta & Emory University School of Medicine, Atlanta, Georgia, USA.
³³ Stravitz-Sanyal Institute for Liver Disease and Metabolic Health at Virginia Commonwealth University, Richmond, Virginia, USA.
³⁴ Division of Pediatric Gastroenterology, Hepatology and Nutrition, Primary Children's Hospital, University of Utah, Salt Lake City, Utah, USA.
³⁵ Division of Pediatric Gastroenterology and Hepatology, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
³⁶ Liver Unit, Birmingham Women's & Children's Hospital NHS Trust, University of Birmingham, Birmingham, UK.
³⁷ Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
³⁸ Department of Paediatrics, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
³⁹ Division of Gastroenterology, Department of Pediatrics, Ramathibodi Hospital Mahidol University, Bangkok, Thailand.
⁴⁰ Section of Hepatology, Department of Gastroenterology, Children's Mercy Kansas City, Kansas City, Missouri, USA.
⁴¹ Division of Pediatric Gastroenterology, Department of Pediatrics, Oregon Health and Science University, Portland, Oregon, USA.
⁴² Division of Pediatric Specialties, Department of Pediatrics, Gynecology, and Obstetrics, Swiss Pediatric Liver Center, University Hospitals Geneva, University of Geneva, Geneva, Switzerland.
⁴³ Schneider Children's Medical Center of Israel, Institute of Gastroenterology, Nutrition and Liver Diseases, Petah Tikva, Israel.
⁴⁴ Department of Paediatric Gastroenterology, Starship Child Health, Auckland, New Zealand.
⁴⁵ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
⁴⁶ Servizio di Epatologia Pediatrica, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
⁴⁷ Department of Pediatric Gastroenterology, University Medical Centre Utrecht, Utrecht, the Netherlands.
⁴⁸ Pediatric Hepatology and Liver Transplant Department, Hospital Universiatri Vall d'Hebron, Barcelona, Spain.
⁴⁹ European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Fondazione IRCCS San Gerardo dei Tintori Hospital, Monza, Italy.
⁵⁰ European Reference Network on Transplantation in Children (ERN-TransplantChild), La Paz Institute of Biomedical Research, Hospital Universitario La Paz, Madrid, Spain.
⁵¹ University of Texas Southwestern Medical Centre in Dallas and Children's Health, Dallas, Texas, USA.
⁵² Department of Pediatric Gastroenterology and Organ Transplant, Koc University School of Medicine, Istanbul, Turkey.
⁵³ Paediatric Gastroenterology Unit, Cruces University Hospital, Bilbao, Spain.
⁵⁴ Pediatric Gastroenterology Hepatology and Nutrition Unit, Hospital Sant Joan de Déu, Esplugues de Llobregat, Spain.
⁵⁵ Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark.
⁵⁶ Meyer Children's Hospital IRCCS, Florence, Italy.
⁵⁷ Division of Paediatric Gastroenterology and Hepatology, London Health Sciences Centre, Children's Hospital, Western University, London, Ontario, Canada.
⁵⁸ Mitera Children's Hospital, Athens, Greece.
⁵⁹ Department of Pediatrics, Children's Nebraska and University of Nebraska Medical Center, Omaha, Nebraska, USA.
⁶⁰ Centro Materno-Infantil do Norte Albino Aroso, Centro Hospitalar Universitário de Santo António, Porto, Portugal.
⁶¹ UCIBIO - Applied Molecular Biosciences Unit, Biochemistry Laboratory, Department of Biological Sciences, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal.
⁶² Division of Pediatric Gastroenterology, Rady Children's Hospital San Diego, University of California San Diego, San Diego, California, USA.
⁶³ Pediatric Gastroenterology, Hepatology and Nutrition, University Medical Center Ljubljana, Ljubljana, Slovenia.
⁶⁴ Department of Pediatrics, Faculty of Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia.
⁶⁵ Pediatric Gastroenterology and Hepatology Division, Hospital Italiano Buenos Aires, Buenos Aires, Argentina.
⁶⁶ Department of Paediatric Gastroenterology, Al Jalila Children's Specialty Hospital, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, UAE.
⁶⁷ Department of Pediatrics, Medical University of Silesia in Katowice, Katowice, Poland.
⁶⁸ Department of Pediatric Gastroenterology, The University of Tennessee Health Science Center, Le Bonheur Children's Hospital, Memphis, Tennessee, USA.
⁶⁹ Massachusetts General Hospital for Children, Boston, Massachusetts, USA.
⁷⁰ University of Rochester Medical Center, Rochester, New York, USA.
⁷¹ Section of Pediatric Gastroenterology, Department of Pediatrics, University of Manitoba, Winnipeg, Canada.
⁷² Pediatric Gastroenterology, Hepatology and Nutrition Department, Istanbul University Istanbul Medical Faculty, Istanbul, Turkey.
⁷³ European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Lisbon, Portugal.
⁷⁴ Pediatric Gastroenterology/Hepatology Center, Lisbon, Portugal.
⁷⁵ Division of Pediatric Gastroenterology, Hepatology and Nutrition/Miami Transplant Institute, University of Miami, Miami, Florida, USA.
⁷⁶ Department of Pediatric Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
⁷⁷ Division of Gastroenterology, Hepatology and Nutrition, Children's Hospital of Eastern Ontario, Ottawa, Canada.
⁷⁸ Department of Hepatology and Gastroenterology, Biodonostia Health Research Institute - Donostia University Hospital, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Universidad del País Vasco (UPV/EHU), San Sebastián, Spain.
⁷⁹ Institute of Liver Studies, King's College London, London, UK.
⁸⁰ Toronto General Hospital University Health Network, Toronto, Canada.
⁸¹ Institute of Health Policy, Management and Evaluation, Toronto, Canada.
⁸² Division of Genomic Diagnostics, Department of Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.

PMID: 40742203
PMCID: PMC12312628
DOI: 10.1111/liv.70251

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.

Keywords: Alagille syndrome; NOTCH2; cholestasis; genetics.

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Conflict of interest statement

Shannon M. Vandriel [consults for Mirum Pharmaceuticals Inc.], Li‐Ting Li, Huiyu She, David A. Piccoli, Irena Jankowska, Piotr Czubkowski, Dorota Gliwicz‐Miedzińska, Emanuele Nicastro, Dominique Debray, Étienne M. Sokal, Tanguy Demaret, Rima L. Fawaz, Silvia Nastasio, Kyung Mo Kim, Seak Hee Oh, Catherine Larson‐Nath [nothing to disclose], Sahana Shankar, Shikha S. Sundaram, Alexander Chaidez, Pinar Bulut, Pier Luigi Calvo, Mureo Kasahara, Niviann Blondet, Eberhard Lurz, Anna‐Maria Kavallar, Emmanuel M. Gonzales, Jérôme Bouligand, Jeffrey A. Feinstein, Susan M. Siew, Michael O. Stormon, Rene Romero, M. Kyle Jensen, Catalina Jaramillo, James E. Squires, Sarah M. Bedoyan, Jane Hartley, Way Seah Lee, Chatmanee Lertudomphonwanit, Henry C. Lin, Yael Mozer‐Glassberg, Amin J. Roberts, Helen M. Evans, Gabriella Nebbia, Pamela L. Valentino, Jesus Quintero Bernabeu, Cigdem Arikan, María Legarda Tamara, Cristina Molera Busoms, Thomas Damgaard Sandahl, Andréanne N. Zizzo, Aglaia Zellos, Ruben E. Quiros‐Tejeira, Ermelinda Santos‐Silva, Jernej Brecelj, Maria Camila Sanchez, Maria Lorena Cavalieri, Christos Tzivinikos, Sabina Wiecek, John Eshun, Zerrin Önal, Cristina Gonçalves, Jennifer Garcia, Seema Alam, Carolina Jimenez‐Rivera, Luis Bujanda [nothing to disclose], Jian‐She Wang [Consultant for Ipsen Biopharmaceuticals Inc., Mirum Pharmaceuticals Inc., and Qing Bile Therapeutics Inc.], Kathleen M. Loomes [Consultant for Mirum Pharmaceuticals Inc., Ipsen Biopharmaceuticals Inc., and Travere Therapeutics Inc.], Lorenzo D'Antiga [Consultant for Mirum Pharmaceuticals Inc., Ipsen Biopharmaceuticals Inc., Alexion, Astra Zeneca, Vivet Therapeutics, Spark, Genespire, Tome, Advanza Pharma], Florence Lacaille [Consultant for Alexion], Björn Fischler [Consultant for Ipsen Biopharmaceuticals Inc.], Henrik Arnell [consultant for Ipsen Biopharmaceuticals Inc., Baxter, Mirum Pharmaceuticals Inc.], Winita Hardikar [Consultant for Ipsen Biopharmaceuticals Inc., Advanz Pharma], Emmanuel Jacquemin [Consultant for CTRS, Theravia and Vivet Therapeutics, France], Noelle H. Ebel [Consultant for Mirum Pharmaceuticals Inc.], Saul J. Karpen [Consultant for Ipsen Biopharmaceuticals Inc., Intercept, Mirum Pharmaceuticals Inc. and Vertex], Deirdre A. Kelly [European Advisory Board for Mirum Pharmaceuticals Inc.; Advisory Board for Intercept & Advanz Pharma], Henkjan J. Verkade [Consultant for Ipsen Biopharmaceuticals Inc., Intercept, Mirum Pharmaceuticals Inc., Orphalan and Vertex], Ryan T. Fischer [Speaker and Consultant for Ipsen Biopharmaceuticals Inc. and Mirum Pharmaceuticals Inc.], Nathalie Rock [Consultant for Mirum Pharmaceuticals Inc.], Wikrom Karnsakul [Consultant for Mirum Pharmaceuticals Inc., Ipsen Biopharmaceuticals Inc., and Travere Therapeutics Inc.], Victorien M. Wolters [Speaker for Mirum Pharmaceuticals Inc.], Amal A. Aqul [Consultant for Mirum Pharmaceuticals Inc., Ipsen Biopharmaceuticals Inc., and Sarepta], Giuseppe Indolfi [Consultant for Mirum Pharmaceuticals Inc.], Kathleen B. Schwarz [Research grant Ipsen Biopharmaceuticals Inc. and Consultant, Mirum Pharmaceuticals Inc], Nanda Kerkar [Advisory Board for Ipsen Biopharmaceuticals Inc. and Mirum Pharmaceuticals Inc.], Quais Mujawar [Advisory Board for Alexion Pharma], Richard J. Thompson [Consultant for Shire, Ipsen Biopharmaceuticals Inc., Mirum Pharmaceuticals Inc., Horizon Pharmaceuticals, Sana Biotechnology, GenerationBio, Retrophin and Qing Bile Therapeutics Inc.], Bettina E. Hansen [Consultant for Mirum Pharmaceuticals Inc., Ipsen Biopharmaceuticals Inc., Chemomab, Calliditas, Intercept, Cyma Bay, unrestricted grants from Cyma bay, Intercept, Mirum Pharmaceuticals Inc., and Ipsen Biopharmaceuticals Inc.], Nancy B. Spinner [Consultant for Mirum Pharmaceuticals Inc., and Travere Therapeutics Inc.], Melissa A. Gilbert [Consultant for Travere Therapeutics Inc.], Binita M. Kamath [Consultant for Mirum Pharmaceuticals Inc., Ipsen Biopharmaceuticals Inc., Third Rock Ventures and Audentes Therapeutics, unrestricted educational grants from Mirum Pharmaceuticals Inc., and Ipsen Biopharmaceuticals Inc.].

Figures

**FIGURE 1**
Ascertainment of the GALA study cohort.

**FIGURE 2**
*NOTCH2* variants reported for ALGS. (A) All disease‐associated *NOTCH2* variants (VOUS, likely pathogenic, and pathogenic; n = 69) identified in this study and those previously reported are plotted along the *NOTCH2* protein. Structural variants and those predicted to have a benign effect on protein function are not included (n = 1). Variants are colour‐coded to distinguish variant types: red (frameshift, n = 11), blue (missense, n = 33), orange (nonsense, n = 7), purple (splice, n = 10), and green (silent, n = 1). Protein domains are depicted using the following colour scheme: teal (EGF‐like), yellow (JAG1‐interacting, EGF‐like), light purple (Lin‐12/Notch repeat; LNR), red (transmembrane), blue (ankyrin repeats) and dark purple (PEST domain). (B) All disease‐associated missense *NOTCH2* variants identified in this study and those previously reported (VOUS, likely pathogenic, and pathogenic; n = 33) are plotted along the *NOTCH2* protein. Variants are colour‐coded according to their location in a functional domain: teal (EGF‐like), yellow (JAG1‐interacting EGF‐like), blue (ankyrin repeats) and grey (no domain). The image was created using Protein Paint (https://proteinpaint.stjude.org/) and BioRender.

**FIGURE 3**
Native liver survival (NLS) and overall survival (OS) rates in individuals with ALGS with a *JAG1* or *NOTCH2* variant. (A) Comparable rates of 10 and 18‐year native liver survival were observed among ALGS patients with a *NOTCH2* (n = 29) or *JAG1* (n = 727) variant who presented with neonatal cholestasis (log‐rank p = 0.192). (B) 10 and 18‐year survival rates for both *NOTCH2* (n = 34) and *JAG1*‐ALGS (n = 902) individuals were found to be statistically indistinguishable (log‐rank p = 0.506).

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References

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Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines

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Phenotypic Divergence of JAG1- and NOTCH2-Associated Alagille Syndrome & Disease-Specific NOTCH2 Variant Classification Guidelines

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