Front Immunol. 2025 ;16 1517347
Elisabetta Toriello,
Rosa Maritato,
Antonio De Rosa,
Maria Valeria Esposito,
Carla Damiano,
Carmen Rosano,
Emilia Cirillo,
Antonietta Tarallo,
Cosimo Abagnale,
Francesca Cillo,
Roberta Romano,
Laura Grilli,
Marika Comegna,
Giancarlo Blasio,
Giancarlo Parenti,
Enrico Maria Surace,
Giuseppe Castaldo,
Claudio Pignata,
Giuliana Giardino.
Wiskott-Aldrich syndrome (WAS) (MIM #301000) is a rare X-linked primary immunodeficiency due to mutations in the WAS gene, characterized by thrombocytopenia with small platelets, eczema, recurrent infections, and an increased incidence of autoimmunity and malignancies. A wide spectrum of mutations has been identified in the WAS gene responsible for a broad variety of clinical phenotypes. By using targeted next-generation sequencing (t-NGS), we identified in a 2-month-old boy with thrombocytopenia and immunological alterations a 4-nucleotide deletion from position +3 to +6 of intron 8 (c.777 + 3_777 + 6delGAGT) of WAS, currently classified on ClinVar as a variant of uncertain significance. The in-vitro characterization of the variant revealed the complete retention of intron 8 in the mature transcript, suggesting a splicing defect due to the loss of a splice donor site at the 5'-end of intron 8. By sequencing the polymerase chain reaction product, we identified a premature stop at codon 269; thus, consequently, no Wiskott-Aldrich syndrome protein (WASp) was detectable in peripheral blood mononuclear cells from the patient. Due to the total absence of a full-length WASp, it is expected that the patient will develop the severe form of the disease, although further monitoring is needed to better define his phenotype.
Keywords: WASP; Wiskott-Aldrich; gene panel; next-generation sequencing (NGS); splice-site mutation