Journal Article

Characterization of a WAS splice-site variant in a patient with Wiskott-Aldrich syndrome

Cirillo, Emilia, Damiano, Carla, Rosano, Carmen, Giardino, Giuliana, Maritato, Rosa, Abagnale, Cosimo, Cillo, Francesca, De Rosa, Antonio, Grilli, Laura, Comegna, Marika, Pignata, Claudio, Blasio, Giancarlo, Parenti, Giancarlo, Romano, Roberta, Surace, Enrico Maria, Esposito, Maria Valeria, Tarallo, Antonietta, Toriello, Elisabetta, Castaldo, Giuseppe

2025

Overview

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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Anticoagulants / Autoimmunity / Blood / Eczema / Gene deletion / gene panel / High-Throughput Nucleotide Sequencing / Humans / Immunodeficiency / Immunology / Infant / Introns / Laboratories / Leukocytes (mononuclear) / Male / Malignancy / Mutation / Next-generation sequencing / next-generation sequencing (NGS) / Patients / Peripheral blood mononuclear cells / Phenotypes / Potassium / Primary immunodeficiencies / Proteins / RNA Splice Sites - genetics / RNA Splicing / Software / splice-site mutation / Thrombocytopenia / WASP / Wiskott-Aldrich / Wiskott-Aldrich syndrome / Wiskott-Aldrich Syndrome - diagnosis / Wiskott-Aldrich Syndrome - genetics / Wiskott-Aldrich Syndrome Protein - genetics