摘要
目的探讨1个van der Woude综合征(VWS)家系的遗传学特征,并为其提供生育指导。方法选取2020年5月因"2次唇腭裂儿妊娠史"在南京鼓楼医院就诊的1例先证者及其家系成员为研究对象。应用家系全外显子组测序(trio-WES)对先证者及其父母进行致病变异筛选,针对候选致病变异进行Sanger测序家系验证(4代共8人)和生物信息学分析。对该家系中的胎儿进行染色体微阵列分析(CMA)以排除拷贝数变异。结果Trio-WES发现先证者及其父亲携带IRF6: c.742G>T(p.G248C)杂合变异,其母亲该位点为野生型。该变异为错义变异,位于重要的蛋白质功能结构区,在正常参考人群基因数据库中未见报道,多种软件预测该变异影响蛋白质结构/功能的可能性较大,与该家系中患者特异性表型高度相关,且Sanger测序结果显示家系中8名成员(包括3名患者)的基因型与表型共分离。依据美国医学遗传学与基因组学学会(ACMG)相关指南,评估为可能致病性变异(PM1+PM2_Supporting+PP1+PP3+PP4)。据此结果对先证者进行植入前遗传学诊断,生育表型正常后代,位点检测及CMA均未见异常。结论本研究明确了IRF6 c.742G>T(p.G248C)杂合变异为该家系的遗传学病因,并为先证者提供了生育指导。
Objective To explore the genetic characteristics of a Chinese pedigree affected with van der Woude syndrome(VWS).Methods A proband who had visited the Drum Tower Hospital Affiliated to Nanjing University Medical School in May 2020 for"two previous pregnancies with cleft lip and palate"was selected as the study subject.Trio-whole exome sequencing(trio-WES)was carried out for the patient.Candidate variants were verified by Sanger sequencing of her pedigree members(8 individuals from four generations)and bioinformatic analysis.Chromosomal microarray analysis(CMA)was used to rule out copy number variations in the fetuses.Results Trio-WES revealed that the proband and her father had both harbored a heterozygous c.742G>T(p.G248C)missense variant of the IRF6 gene,for which her mother was of the wild type.The variant was located in a region with important functions and has not been reported previously.Prediction with several software suggested that it is likely to have a significant impact on the protein structure/function and is highly correlated with the specific phenotypes in this pedigree.Sanger sequencing confirmed co-segregation of the genotypes and phenotypes in the pedigree.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),this variant was rated as likely pathogenic(PM1+PM2_Supporting+PP1+PP3+PP4).Based on the above results,pre-implantation genetic diagnosis was carried out for the proband,which has led to birth of a healthy offspring with normal results for both site testing and CMA.Conclusion The IRF6:c.742G>T(p.G248C)heterozygous variant probably underlay the VWS in this pedigree.Above finding has also enabled reproductive guidance for the proband.
作者
朱湘玉
曹培暄
朱雨捷
李洁
Zhu Xiangyu;Cao Peixuan;Zhu Yujie;Li Jie(Department of Obstetrics and Gynecology,Drum Tower Hospital Affiliated to Nanjing University Medical School,Nanjing,Jiangsu 210008,China)
出处
《中华医学遗传学杂志》
CAS
CSCD
2023年第12期1517-1520,共4页
Chinese Journal of Medical Genetics
