Clinical aspects and genetic analysis of taiwanese patients with wiskott-Aldrich syndrome protein mutation: the first identification of x-linked thrombocytopenia in the chinese with novel mutations.
BACKGROUND
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by microthrombocytopenia, eczema, and recurrent infections. However, the more than 500 patient mutations described are mainly based on Caucasian and Japanese populations. This study investigated Taiwanese patients with WASP mutations since 1985 as part of a long-term comprehensive study in primary immunodeficiency diseases (PIDs) covering 23 million inhabitants.


METHODS
Clinical manifestations, immunologic functions, and WASP gene sequencing and expressions were analyzed in WAS patients. And, those patients with idiopathic thrombocytopenic purpura and "small" thrombocytopenia were enrolled.


RESULTS
Of 16 patients studied in 1993-2009, 12 presented as classic WAS phenotype and four had X-linked thrombocytopenia (XLT). Almost all correlated to the WASP expression level and severity of infections. Causes of mortality in the 12 classic WAS patients were mass bleeding, Staphylococcus aureus sepsis, and cytomegalovirus (CMV) pneumonitis in three non-transplant cases, and EBV-associated lymphoproliferative disorder and CMV pneumonitis in two non-engrafted transplant patients. Splicing mutations of Int 8 (+5) G>A in cousins and insertion of 1023 C in unrelated families presented as both XLT and classic WAS phenotype in the same mutations. Four XLT patients, including two novel mutations of 1023 Ins C (in 2) and "double" missense mutations of 1378 C>T and 1421 T>C had relatively higher CD4+ memory cells and/or activated lymphocytes (CD3+CD69+) compared with those of classic WAS patients.


CONCLUSIONS
The lower ratio of XLT to classic WAS patients underestimates the burden of Taiwanese patients with WASP mutations, especially the XLT phenotype. A clustering pattern on exon 1 and five unique mutations (deletion of 45-48 ACCA, IVS 1 (-1) G>C, large deletion of promoter and exon 1 and 2, insertion 1023 C, and 1378 C>T and 1421 T>C) explain the genetic variations in different ethnic groups, despite the possibility of selection and ascertainment bias.
Lee
Wen-I
WI
Primary Immunodeficiency Care and Research (PICAR) Institute, Chang Gung Memorial & Children's Hospital and University College of Medicine, #5 Fu-Shing St. (Pediatric Office 12 L), Kwei-Shan, Taoyuan, Taiwan. wen2707@hotmail.com
Huang
Jing-Long
JL
Jaing
Tang-Her
TH
Wu
Kang-Hsi
KH
Chien
Yin-Hsiu
YH
Chang
Kuei-Wen
KW
D044466:Asian People; D002423:Cause of Death; D004252:DNA Mutational Analysis; D005190:Family; D040181:Genetic Diseases, X-Linked; D006801:Humans; D009154:Mutation; D013624:Taiwan; D013921:Thrombocytopenia / Q000235:genetics*; D014923:Wiskott-Aldrich Syndrome / Q000208:ethnology / Q000235:genetics; D051316:Wiskott-Aldrich Syndrome Protein / Q000235:genetics*
D051316:Wiskott-Aldrich Syndrome Protein