An asymptomatic WASF1 truncation reveals pathogenic mechanism and therapeutic strategy for neurodevelopmental disorders

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Abstract
Introduction: Wiskott–Aldrich syndrome protein family member 1 ( WASF1 ) truncating variants, such as c.1516C>T (p.Arg506Ter), are established causes of neurodevelopmental disorders (NDDs), but their underlying pathogenic mechanism remains debated. This study aimed to clarify the disease mechanism and identify potential therapeutic leads. Methods: We characterized a novel, asymptomatic WASF1 truncating variant (c.873delA) and compared its clinical and molecular consequences with those of the known pathogenic c.1516C>T variant. To target the likely pathogenic mutant protein, we performed high‑throughput virtual screening of the ZINC20 database. Results: Despite a similar reduction in wild‑type protein levels, the c.873delA variant did not cause neurological symptoms, in contrast to c.1516C>T. This observation supports a dominant‑negative, gain‑of‑function, or altered protein function mechanism rather than simple haploinsufficiency; however, the precise mechanism could not be definitively resolved from the available genetic and protein expression data. Virtual screening identified ZINC000101023849 as a high‑affinity lead compound with favorable drug‑like properties. Discussion: This study provides key evidence that WASF1 ‑related NDDs likely arise from a non‑haploinsufficiency mechanism and delivers a promising chemical lead for targeted therapy development. Further studies are needed to confirm the exact pathogenic mechanism and to validate the therapeutic potential of the identified compound.

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