HIGH PREVALENCE OF NONSENSE, FRAME-SHIFT, AND SPLICE-SITE MUTATIONS IN 16 PATIENTS WITH FULL-BLOWN WISKOTT-ALDRICH SYNDROME

Wiskott-Aldrich syndrome (WAS) is a fully penetrant X-linked recessive disorder characterized by immunodeficiency, thrombocytopenia, and sev ere eczema. WAS is a life-threatening disease, with a poor quality of life and high mortality rate in childhood, The gene responsible for th e disease has been localized to the proximal short arm of the X-chromo some and recently isolated through positional cloning and named WAS pr otein (WASP), We have characterized 17 WAS families. We have developed a rapid, nonradioactive screening protocol for identifying WASP gene alterations in genomic DNA, Our method allows simultaneous evaluation of single strand conformation polymorphism and heteroduplex formation. We have identified 15 novel mutations that involve single basepair ch anges, or small insertions or deletions, all of which result in premat ure stop codon, frame shift with secondary premature stop codon, or sp lice site defect, These studies document the considerable heterogeneit y of the location of mutations in the WASP gene causing full-blown WAS and show the efficiency and rapidity of a screening approach for muta tion identification in WAS that will be useful for carrier detection a nd prenatal diagnosis. (C) 1995 by The American Society of Hematology.