Wiskott-Aldrich syndrome: a study of 577 patients defines the genotype as a biomarker for disease severity and survival

作者：Tanja C. Vallée, Jannik S. Glasmacher, Hannes Buchner, Peter D. Arkwright, Uta Behrends, Anastasiia V. Bondarenko, Michael J. Browning, David Kyle Buchbinder, Alessandro Cattoni, Liudmyla I. Chernyshova, Peter Čižnár, Theresa S. Cole, Wojciech Czogała, Gregor Dueckers, John David M. Edgar, Fatih Erbey, Anders L. Fasth, Francesca Ferrua, Renata Formánková, Eleonora Gambineri, Andrew Richard Gennery, Frederick D. Goldman, Luis Ignacio González‐Granado, Carsten Johan Heilmann, Tarja Heiskanen‐Kosma, Hanna Juntti, Leena Kainulainen, Hirokazu Kanegane, Neslihan Edeer Karaca, Sara Şebnem Kılıç, Christoph A. Klein, Sylwia Kołtan, Irina V. Kondratenko, Isabelle Meyts, Gulnara Nasrullayeva, Lucia Dora Notarangelo, Srdjan Pašić, Isabelle Pellier, Claudio Pignata, Siraj Misbah, Ansgar Schulz, Gesmar Rodrigues Silva Segundo, Anna Yu. Shcherbina, Mary Anne Slatter, Robert A. Sokolic, Pere Soler‐Palacín, Polina Stepensky, Joris M. van Montfrans, Samppa J. Ryhänen, Beata Wolska‐Kuśnierz, John Bernard Ziegler, Xiaodong Zhao, Alessandro Aiuti, Hans D. Ochs, Michael H. Albert · 发表于：Blood · 年份：2024 · DOI：10.1182/blood.2023021411 · 被引用次数：38 · 研究领域：Cell Adhesion Molecules Research、Cellular Mechanics and Interactions、Cancer Genomics and Diagnostics

ABSTRACT: Wiskott-Aldrich syndrome (WAS) is a multifaceted monogenic disorder with a broad disease spectrum and variable disease severity and a variety of treatment options including allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy (GT). No reliable biomarker exists to predict disease course and outcome for individual patients. A total of 577 patients with a WAS variant from 26 countries and a median follow-up of 8.9 years (range, 0.3-71.1), totaling 6118 patient-years, were included in this international retrospective study. Overall survival (OS) of the cohort (censored at HSCT or GT) was 82% (95% confidence interval, 78-87) at age 15 years and 70% (61-80) at 30 years. The type of variant was predictive of outcome: patients with a missense variant in exons 1 or 2 or with the intronic hot spot variant c.559+5G>A (class I variants) had a 15-year OS of 93% (89-98) and a 30-year OS of 91% (86-97), compared with 71% (62-81) and 48% (34-68) in patients with any other variant (class II; P < .0001). The cumulative incidence rates of disease-related complications such as severe bleeding (P = .007), life-threatening infection (P < .0001), and autoimmunity (P = .004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (P = .6) was not different between classes I and II. It confirms the spectrum of disease severity and quantifies the risk for specific disease-related complications. The class of the variant is ...