Wiskott-Aldrich syndrome/X-linked thrombocytopenia in China: Clinical characteristic and genotype-phenotype correlation.
BACKGROUND
Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by mutations of the WAS gene. The genotype-phenotype association of WAS and XLT have not been fully elucidated. Here, we established the largest database of WAS in China to further determine the potential correlation between genotype and phenotype and long-term outcome.


METHODS
We collected clinical data of 81 WAS/XLT patients, analyzed mutations of WAS gene at the genomic DNA and transcriptional/translational levels, and quantified three different patterns of WAS protein (WASp) expression in PBMCs by flow cytometry.


RESULTS
There were 60 unique mutations identified, including 20 novel mutations and eight hotspots, from 75 unrelated families with a total of 81 affected members. Nearly all the patients with XLT had missense mutations and were WASp-positive in the peripheral cells, while only half of the patients with missense mutations exhibited the XLT phenotype and detectable WASp. In contrast, patients with nonsense mutations, deletions, insertions, and complex mutations were WASp-negative and developed the classic WAS phenotype. An equal number of patients with splice anomalies were either WASp-positive or WASp-negative. Long-term survival rates were lower in WASp-negative patients compared to WASp-positive patients.


CONCLUSIONS
The clinical phenotype of classic WAS or milder XLT and long-term outcome are potentially influenced by the effect of these defects on gene transcription and translation. Patients with missense mutations allowing expression of mutated WASp and those with splice anomalies, which result in generation of multiple products, including normal WASp, present the attenuated XLT phenotype and show better prognosis.
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China.
Da-Wei
DW
Liu
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China.
Zhi-Yong
ZY
Zhang
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China.
Qin
Q
Zhao
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China.
Li-Ping
LP
Jiang
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China.
Wei
W
Liu
Department of Paediatrics & Adolescent Medicine, LKS Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
Wen-Wei
WW
Tu
Department of Cell Biology & Molecular Genetics, University of Maryland, College Park, Maryland.
Wen-Xia
WX
Song
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital, Chongqing Medical University, Chongqing, China.
Xiao-Dong
XD
Zhao
D017668:Age of Onset; D002675:Child, Preschool; D002681:China / Q000453:epidemiology; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D004200:Diseases in Twins / Q000235:genetics; D005434:Flow Cytometry; D005786:Gene Expression Regulation; D040181:Genetic Diseases, X-Linked / Q000453:epidemiology / Q000235:genetics*; D005838:Genotype; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010641:Phenotype; D014176:Protein Biosynthesis; D015996:Survival Rate; D013921:Thrombocytopenia / Q000453:epidemiology / Q000235:genetics*; D014158:Transcription, Genetic; D016896:Treatment Outcome; D014923:Wiskott-Aldrich Syndrome / Q000453:epidemiology / Q000235:genetics* / Q000628:therapy; D051316:Wiskott-Aldrich Syndrome Protein / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*
C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein
WASp; Wiskott-Aldrich syndrome; clinical characteristic; genotype-phenotype correlation; mutation analysis