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目的分析24例Wiskott-Aldrich综合征(Wiskott-Aldrich syndrome,WAS)患儿基因型与临床表现型关系。方法收集24例WAS患儿临床资料,进行临床表现型评分。流式细胞术检测患儿外周血单个核细胞(peripheral bloodmononuclear cells,PBMCs)、WAS蛋白(Wiskott-Aldrich syndrome protein,WASP)的表达。对WASP基因进行直接测序,并分析基因型与表现型的关系。结果 24例患儿系男性,2例临床表现型评分为2分,为X连锁血小板减少症(X-linkedthrombocytopenia,XLT);其余患儿评分均≥3分,为典型WAS。除1例WASP正常表达,2例WASP表达减少外,其余患儿WASP均为阴性。发现WASP基因突变包括7例错义突变、4例无义突变、6例缺失突变及7例拼接位点突变。共发现基因突变21种、新发突变3种,即180 C>T(A49V)、342-343del CA(S103fsX121)、IVS7+2 T>C。发现已报道的热点突变6种,包括291 G>A(R86H)、291G>T(R86L)、1035del G(G334fsX444)、665 C>T(R211X)、IVS6+5 G>A、IVS8+1 G>A。错义突变患儿2例为XLT,其余均为典型WAS。无义突变、缺失突变及拼接位点突变的患儿均为评分3～5分的典型WAS,部分患儿表现型严重。结论 WASP下游区域的基因突变、无义、缺失、拼接位点突变类型则更可能导致WASP表达缺失、不稳定或截短型WASP,临床表型多为典型WAS。环境因素可导致患儿表现型加重。
Objective To analyze the relationship between genotypes and clinical phenotypes in 24 Wiskott-Aldrich syndrome (WAS) children. Methods The clinical data of 24 WAS children were collected and scored for clinical phenotype. Flow cytometry was used to detect the expression of peripheral blood mononuclear cells (PBMCs) and WAS protein (WASP) in children. The WASP gene was sequenced directly and the relationship between genotypes and phenotypes was analyzed. Results Twenty-four children were male and 2 of them were clinically phenotype score of X-linked thrombocytopenia (XLT). The remaining children were all score ≥3, which was typical WAS. Except for the normal expression of WASP in 1 case and the decrease of WASP expression in 2 cases, WASP in the remaining cases were all negative. WASP gene mutations were found to include seven missense mutations, four nonsense mutations, six deletion mutations and seven splicing site mutations. A total of 21 gene mutations and 3 new mutations were found, namely 180 C> T (A49V), 342-343del CA (S103fsX121) and IVS7 + 2 T> C. Six hotspot mutations were reported including 291G> A (R86H), 291G> T (R86L), 1035delG (G334fsX444), 665C> T (R211X), IVS6 + 5G> A, IVS8 + 1G > A. Two cases of missense mutation in children with XLT, the rest were typical WAS. Nonsense mutations, deletion mutations and splicing site mutations in children were scoring 3 to 5 typical WAS, some children with severe manifestations. CONCLUSION: WASP gene mutation, nonsense, deletion and splicing site mutation types in WASP downstream region are more likely to cause WASP expression loss, unstable or truncated WASP, and clinical phenotype is typical WAS. Environmental factors can lead to exacerbations in children.