先天性晶状体脱位一家系致病基因突变筛查

Screening for pathogenic gene in a Chinese family with congenital ectopia lentis

目的分析一先天性晶状体脱位家系的致病基因突变与相关临床表型的关系。方法前瞻性病例研究。选取就诊于临沂市人民医院眼科门诊的1个先天性晶状体脱位家系和100名健康志愿者,抽取他们的外周血5 ml并提取基因组DNA。采用高通量测序对先证者进行可能的致病基因的筛查,而后用Sanger测序法在其余家系成员和100位健康人上验证。生物信息学用于预测突变基因的功能效应。结果该家系遗传方式符合常染色体显性遗传。先证者表型为双眼晶状体向颞上方脱位,在其原纤维蛋白基因-1(fibrillin-1 gene,FBN1)第33个外显子第3965位碱基有1个A>G的杂合错义突变,此突变导致蛋白第1322位的天冬氨酸被甘氨酸取代(D1322G),这一突变也存在该家系的其他晶状体脱位患者,在其余家庭成员和100位健康人中未发现有该突变。可见,该基因突变与疾病表型完全共分离。SIFT和Polyphen-2等生物信息学预测这种突变对蛋白质功能的影响很可能是有害的。结论FBN1基因c.3965A>G(p.D1322G)是该先天性晶状体脱位家系的致病突变,这是首次在国内发现的致病基因突变。

Objective To analyze the relationship between gene mutation and clinical phenotype in a Chinese family with ectopia lentis(EL).Methods Prospective series case study.Participants from an ectopia lentis family and 100 healthy volunteers from the Department of Ophthalmology at the Linyi people's hospital were included.A 5 ml of peripheral blood was collected and genomic DNA was extracted per standardized protocol.The DNA sample of the probands in this family were analyzed by targeted exome sequencing,which was then validated by Sanger sequencing in the remaining family members and 100 controls.The functional effect of mutant genes was investigated via bioinformatics analysis.Results The inheritance pattern of the family was autosomal dominant.The phenotype of the proband was bilateral lens dislocation to the superior temporal region.A heterozygous missense mutation of A>G was found at 3965 base of exon 33of fibrillin-1 gene(FBN1),which resulted in the substitution of glycine for aspartate at position 1322(D1322G).This mutation also existed in other EL patients in this family.No mutation was found in other family members or the 100 healthy people.It can be seen that the gene mutation was completely co-segregated form the disease phenotype.Bioinformatics such as SIFT and Polyphen-2 predict that the effect of this mutation on protein function might be harmful.Conclusions FBN1 gene c.3965A>G(p.D1322G)is the pathogenic mutation of congenital lens dislocation,which is the first pathogenic gene mutation found in EL patients from China.