De novo variant in tyrosine kinase SRC causes thrombocytopenia: case report of a second family

A germline heterozygous gain-of-function <i>p</i>.E527K variant in tyrosine kinase SRC was previously found to cause thrombocytopenia, myelofibrosis, bleeding, bone pathologies, premature edentulism and mild facial dysmorphia in nine patients of a single pedigree. Because of this variant, SRC loses its self-inhibitory capacity, causing constitutively active SRC expression in platelets. These patients have fewer and heterogeneous-sized platelets that are hyporeactive to collagen. We now report a 5-year-old girl with syndromic thrombocytopenia due to the same SRC-E527K variant that occurs <i>de novo</i>. A bone marrow biopsy, blood smear analysis, platelet aggregations, flow cytometric analysis of <i>P</i>-selectin, SRC expression and tyrosine phosphorylation studies were performed to confirm the similarities between the two families. This study strengthens our previous finding that hyperactive SRC kinase results in mild platelet dysfunction and thrombocytopenia with hypogranular platelets and further expands the clinical description of this syndrome to improve early recognition.

既往研究在一个单一家系的9例患者中，发现酪氨酸激酶SRC（SRC）存在种系杂合功能获得性p.E527K变异，该变异可导致血小板减少症、骨髓纤维化、出血、骨骼病变、早发性无牙症及轻度面部畸形。该变异使SRC丧失自身抑制能力，引发血小板中SRC呈组成型激活表达。此类患者的血小板数量减少且体积不均一，对胶原的反应性低下。本研究报道1例携带新生（de novo）SRC-E527K变异的5岁女童，其患有综合征性血小板减少症。研究者通过骨髓活检、血涂片分析、血小板聚集试验、P选择素（P-selectin）流式细胞术分析、SRC表达检测及酪氨酸磷酸化研究，验证了本次病例与既往单一家系患者的表型相似性。本研究进一步强化了既往发现：过度激活的SRC激酶可导致轻度血小板功能障碍及伴颗粒不足性血小板的血小板减少症，并扩充了该综合征的临床表型描述，以提升早期识别效率。