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Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder caused by deleterious variants in the WAS gene, which encodes the WASP protein essential for actin cytoskeleton regulation in hematopoietic cells. It is characterized by microthrombocytopenia, eczema, and immunodeficiency, often presenting with severe bleeding, infections, and atopic dermatitis in infancy. A milder phenotype, X-linked thrombocytopenia (XLT), is associated with hypomorphic missense mutations and residual WASP expression. Female carriers are usually asymptomatic due to skewed X-chromosome inactivation but may manifest disease when inactivation is non-random. The clinical spectrum correlates strongly with genotype, guiding prognosis and management. Early diagnosis via genetic and functional testing enables timely hematopoietic stem cell transplantation or gene therapy.
Inheritance is X-linked recessive with co-segregation of pathogenic alleles demonstrated in at least 6 families. Over 577 patients have been molecularly characterized, revealing more than 62 unique mutations across all WAS exons, including missense, nonsense, frameshift, splice-site, and regulatory variants. A recurrent hotspot, c.37C>T (p.Arg13Ter), has been identified in both classic WAS and XLT ([PMID:7579347]). Founder and recurrent variants such as c.559+5G>A are well documented in multiple ethnic groups. Carrier screening and prenatal diagnosis employ sequence analysis and WASP expression assays, confirming genotype–phenotype relationships.
Truncating mutations and complex indels typically lead to classic WAS with absent WASP and severe immunodeficiency, whereas missense and splice-site anomalies produce variable residual protein and an attenuated XLT phenotype. Quantitative genotype–phenotype correlation in a cohort of 577 patients showed that class I variants (exons 1–2 missense, c.559+5G>A) exhibit 93% survival at 15 years and reduced bleeding and infection complications ([PMID:38579284]). Such data underpin the use of mutation class as a biomarker for disease severity and long-term survival. Population carrier frequency remains low. The extensive genetic evidence fulfills ClinGen criteria for a definitive association.
Functional studies reveal that WASP interacts with the Arp2/3 complex to nucleate actin filament assembly, regulated by an autoinhibitory domain and Cdc42 binding. Loss- and gain-of-function mutations in vitro and in vivo impair T-cell chemotaxis, dendritic cell trafficking, and megakaryocyte maturation ([PMID:15774550]). Zinc-finger nuclease knockout in K562 cells recapitulates megakaryocytic defects, validating human cellular models. Tyrosine phosphorylation of Y293 and protein stability modulate WASP activity and immune synapse formation. Animal and cellular models consistently demonstrate that haploinsufficiency of WASP underlies pathogenesis. These concordant experimental data support a moderate level of functional evidence.
No significant conflicting evidence has been reported. Somatic reversion and mosaicism highlight selection for functional WASP-expressing cells but do not contradict causality. Rare autosomal dominant variants affecting related pathways have been described but do not undermine X-linked inheritance. Second-site revertant mutations further reinforce the selective advantage of corrected alleles in vivo.
Integration of genetic and functional findings confirms a definitive association between WAS and Wiskott-Aldrich syndrome. Genetic testing of WAS is clinically valuable for early diagnosis, carrier screening, and guiding curative therapies. Functional assays measuring WASP expression by flow cytometry complement genetic analysis in ambiguous cases. Mutational hotspots and variant classes inform diagnostic and prognostic frameworks. The genotype drives therapeutic decisions, underscoring WAS as a predictive and diagnostic biomarker.
Gene–Disease AssociationDefinitiveExtensive mutational spectrum in >577 patients with robust genotype–phenotype correlation Genetic EvidenceStrongOver 62 unique variants in multiple independent probands; co-segregation in families; reached genetic evidence cap Functional EvidenceModerateConcordant in vitro and in vivo assays demonstrating WASP’s role in actin dynamics and immune cell function |