遗传性球形红细胞增多症家系ANK1基因新发剪切位点突变的不典型表型及表型差异探讨 [中文引用][英文引用]

目的 对疑似遗传性球形红细胞增多症家系进行基因检测，探讨家系成员的不典型表型及表型差异。方法 利用核心家系医学外显子测序进行基因突变检测，一代测序验证结果。根据家系检测发现的基因突变情况，充分知情同意后行第二胎产前诊断。结果 外显子测序发现先证者ANK1基因存在一个剪切位点c.4381+1delG杂合突变，遗传自父亲。该突变位点在物种间高度保守，生物信息学软件预测提示可能影响剪切，本实验室参考人群（2000人）外显子数据中未发现此突变位点，提示人群频率低。产前诊断结果提示胎儿遗传了父亲的基因突变。结论 在遗传性球形红细胞增多症家系中首次发现ANK1基因c.4381+1delG杂合突变，数据库中未见报道，丰富了ANK1基因突变谱。先证者及父亲携带基因突变，但没有典型的临床表现且表型存在差异，可能是因为该突变未导致锚蛋白功能全部丧失，红细胞膜损伤程度较低，不同个体间存在遗传背景差异导致表型差异。胎儿遗传了父亲突变位点，为胎儿今后的发病风险提供遗传咨询信息。

Objective To detect the suspected hereditary spherocytosis family gene mutation and discuss the probable cause of atypical phenotypes and phenotypic differences. Methods The core family medical exome sequencing was used for gene mutation detection and Sanger sequencing verified the results. Prenatal diagnosis of the second fetus was performed with full informed consent according to the genetic mutation found in the family. Results Exome sequencing found that there was a split-site heterozygous mutation c.4381+1delG in ANK1 gene in proband, which was inherited from her father. The position is highly conserved between species and the prediction of bioinformatics software suggested that the splicing might be affected. The mutation was not found in the exome sequencing database of the reference population (2000 people) in our laboratory, suggesting low population frequency. Prenatal diagnosis indicated that the fetus inherited the mutation from the father. Conclusions The new mutation c.4381+1delG of ANK1 gene was found in a family with hereditary spherocytosis, which enriches the mutation spectrum of ANK1 gene. The proband and the father carried the mutation, but they don’t have typical clinical manifestation and the phenotype was different, which may be caused by the mutation did not lead to the complete loss of anchor protein function, the degree of erythrocyte membrane damage was mild, and the genetic background variation between different entities result in variable phenotype. The foetus inherited the paternal mutation, which provides genetic counseling information for the disease risk.