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

Tanja C. Vallée, Jannik S. Glasmacher, Hannes Buchner, Peter D. Arkwright, Uta Behrends, Anastasia Bondarenko, Michael J. Browning, David Buchbinder, Alessandro Cattoni, Liudmyla Chernyshova, Peter Ciznar, Theresa Cole, Wojciech Czogała, Gregor Dueckers, John David M. Edgar, Fatih Erbey, Anders Fasth, Francesca Ferrua, Renata Formankova, Eleonora GambineriAndrew R. Gennery, Frederick D. Goldman, Luis I. Gonzalez-Granado, Carsten Heilmann, Tarja Heiskanen-Kosma, Hanna Juntti, Leena Kainulainen, Hirokazu Kanegane, Neslihan E. Karaca, Sara S. Kilic, Christoph Klein, Sylwia Kołtan, Irina Kondratenko, Isabelle Meyts, Gulnara M. Nasrullayeva, Lucia D. Notarangelo, Srdjan Pasic, Isabelle Pellier, Claudio Pignata, Siraj Misbah, Ansgar Schulz, Gesmar R. Segundo, Anna Shcherbina, Mary Slatter, Robert Sokolic, Pere Soler-Palacin, Polina Stepensky, Joris M. van Montfrans, Samppa Ryhänen, Beata Wolska-Kuśnierz, John B. Ziegler, Xiaodong Zhao, Alessandro Aiuti, Hans D. Ochs, Michael H. Albert*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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 a biomarker to predict the outcome for patients with WAS.

Original languageEnglish
Pages (from-to)2504-2516
Number of pages13
JournalBlood
Volume143
Issue number24
DOIs
Publication statusPublished - 13 Jun 2024

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