Carriers of Wiskott-Aldrich Syndrome

First-ever International Study on the Clinical Spectrum of WAS Carriers

We are proud to share the publication of the first-ever study examining the clinical spectrum of Wiskott-Aldrich Syndrome (WAS) carriers: https://doi.org/10.1016/j.clim.2025.110658.

This study was spearheaded by the Wiskott-Aldrich Foundation and conducted in collaboration with the Primary Immune Deficiency Treatment Consortium (PIDTC) and the Immune Deficiency Foundation (IDF). It came about because carriers have been raising important questions about their own health—and we listened.

We are deeply grateful to all carriers who participated in the survey, and especially to the group of carriers who helped develop and beta-test it. Their input shaped the study and will serve as a foundation for future research.

Thanks to this study, we are beginning to have answers to important questions about the health of WAS carriers. While this represents an important first step, more research is needed to fully understand the range of symptoms, determine health risks for carriers and create a plan for the management of symptomatic carriers.  Last, but not least is the importance of determining if carriers can be donors and if so, what testing should be done to determine if the carrier can be a safe donor.  We hope to start more studies in 2026.

A special thank you to the PIDTC for their collaboration and support, which made this study possible.

Title: Clinical spectrum of Wiskott‑Aldrich syndrome carriers: Self‑reported survey 

Background: Over the years, WAS carriers have expressed concerns about their health and the potential that the mutated WAS gene could be contributing to health concerns including thrombocytopenia, possibility of increased risk for infections, autoimmune conditions and some have expressed concerns about the possibility of increased risk of solid tumors.  Carriers have also raised questions about the suitability of the use of carriers as donors for patients with WAS. Since the identification of the WAS gene in 1994, a few reports have described carriers with skewed X-chromosome inactivation in association with symptoms of WAS (thrombocytopenia, eczema, infections), though prevalence and severity of the disease burden in carriers has not been described previously. There had not been a systematic study conducted to address these concerns. The Wiskott-Aldrich Foundation has been listening to these requests and spearheaded this study to get answers for our carriers.

Female Carrier Genetics: Most mothers of boys with WAS are carriers of the mutated WAS gene while up to a third of mutations are de novo² or new mutations in the child and the mother is not a carrier.  Female carriers of WAS carry the mutated WAS gene on one of their X chromosomes and the normal WAS gene on their second X chromosome.  One X chromosome is derived from the father and the other from the mother.  Very early in fetal life ( as early as 1 week after conception) one X chromosome is inactivated in a process referred to as lyonization.  The process of inactivation renders one of the X chromosomes dormant while the other remains active.  Once an X chromosome has been inactivated, that particular X chromosome will remain inactive for the rest of the carriers life.  

The choice of which X chromosome is inactivated is random, ie, 50% of  X chromosome with the normal gene and 50% of the X chromosome with the mutated WAS gene should be inactivated.  However, this is not always the case and in many instances the inactivation is skewed.  It can be skewed toward the X chromosome with the mutated WAS gene or toward the X chromosome with the normal WAS gene. At present there is not enough information to ascertain which pathway is taken for any particular patient.  Explained below are scenarios when these different types of inactivation happen and the resulting effect on the carrier.  

1.  Random X inactivation:  This is where either X chromosome (mutated or normal X) is randomly inactivated.  This results in the carrier having two populations of blood cells, one carrying the mutated X and one carrying the normal X chromosome. It is postulated that this type of inactivation usually occurs when the mutation is a Type I mutation (ie, the sons show less severe phenotype, previously referred to as XLT or Mild WAS).  Carriers may exhibit mild or no WAS related symptoms.  

2. Skewing: 

a. Skewed toward the normal X:  Here, the mutated X chromosome is preferentially inactivated resulting in the carriers having almost none to some abnormal blood cells, depending on the percentage of skewing.  It is postulated that this type of inactivation is more commonly seen in carriers carrying a Type II mutation (i.e. the sons show severe phenotype, patients with severe WAS).  Carriers who are skewed toward the normal X chromosome exhibit no symptoms of WAS.

b. Skewed toward the mutated X chromosome³,⁴,⁵ Here the normal X chromosome is preferentially inactivated resulting in carriers having WAS related symptoms.  In general, this type of skewing is uncommon and can result in the female carrier having WAS.