IL2RG基因新突变致X-连锁重症联合免疫缺陷病二例及产前诊断研究

Mutation analyses and prenatal diagnosis in two families of X linked severe combined immunodeficiency caused by IL2RG gene novel mutation

目的 对2个X-连锁重症联合免疫缺陷病（X-SCID）家系进行致病基因突变分析及产前诊断.方法 收集2012年1月至2013年2月郑州大学第一附属医院就诊的2个X-SCID家系中患者及其家庭成员的外周血,提取基因组DNA,应用PCR扩增和直接测序方法对2个X-SCID家系成员进行白细胞介素2受体基因IL2RG基因测序,分析IL2RG基因外显子区和剪切区DNA序列改变情况,同时选择100名健康对照个体进行IL2RG基因序列分析.在确定每个家系基因型后,对家系1中的高危胎儿抽取绒毛进行产前诊断.对家系1中可疑女性进行携带者检测.结果 2个X-SCID家系分别发现1种IL2RG基因新突变.家系1中,患者及其母亲携带IL2RG基因c.361-363delGAG（p.E121del）突变;家系2中,先证者母亲携带IL2RG基因c.510-511insGAACT（p.W173X）杂合突变.c.361-363delGAG（p.E121del）和c.510-511 insGAACT（p.W173X）突变均为新发现的突变,100名健康个体X-SCID基因相应区域测序,未发现有上述同样序列改变.对明确致病突变的家系1中胎儿行孕早期产前诊断,胎儿为女性,未携带致病突变,家系1夫妇选择继续妊娠,胎儿娩出后随访结果与产前诊断结果一致.对家系1中可疑女性Ⅱ-3行携带者检测,证实为非携带者.结论 发现2个IL2RG基因新变异,IL2RG基因p.E121del和p.W173X突变是家系1和家系2患者的致病原因;有X-SCID生育史的夫妇再次生育时,应用基因测序技术行产前IL2RG基因突变分析可以有效地预防患儿出生,并且可进行可疑女性的携带者检测.

Objective To evaluate the diagnostic feasibility of mutation analysis and prenatal genetic diagnosis genetic analysis of IL2RG gene in two families with a birth history of X-linked severe combined immunodeficiency （X-SCID）.Methods Blood samples of a male infant patient of X-SCID and his mother in family 1 and the parents of another deceased child with X-SCID in family 2 from January 2012 to February 2013 were collected.Eight exons comprising IL2RG open reading frame and their exon/intron boundaries were analyzed by bi-directional direct sequencing of polymerase chain reaction （PCR） products.Prenatal genetic diagnoses were performed by chorionic villus sampling after the genotypes of maternal probands were identified in family 1.Results Two mutations of IL2RG gene were identified in these two families.The c.361-363delGAG （p.E121del） mutation was identified in family 1.The c.510-511insGAACT （p.W173X） mutation appeared in family 2.The two mutations of c.361-363delGAG （p.E121del） and c.510-511insGAACT （p.W173X） were novel.The two novel mutations were absent in 100 normal controls.The pregnancy in family 1 continued and the infant showed no symptom of X-SCID at 1 year after birth.The aunt （Ⅱ-3） of proband in family 1 was not a carrier.The female fetus in family 1 had no mutation.Conclusions Two novel mutations of c.361-363delGAG（p.E121del） and c.510-511insGAACT （p.W173X） in IL2RG gene may be a major cause of disease in two families with X-SCID.And direct sequencing of IL2RG gene provides genetic counseling,prenatal diagnosis and carrier screening for families with X-SCID.