常染色体显性遗传Meill-Machesai综合征基因型及临床表型分析

Mutation analysis of the autosomal dominant Weill-Marchesani syndrome and genotype-phenotype review

目的对1例Weill-Marchesani综合征（WMS）家系的致病基因进行筛查，并探讨常染色体显性遗传性WMS基因型与表型的关系。方法于2016年9月至2017年7月在河南省立眼科医院收集河南省疑似WMS一家系，收集该家系成员外周血样本及临床资料，采用全外显子组测序（WES）技术对家系成员致病基因进行筛查，分析晶状体脱位相关基因（FBN1、ADAMTSL2、ADAMTSL4、TGFBR2、CBS、ADAMTS10和ADAMTS17）的变异，并行相关基因多重连接探针扩增技术（MLPA）检测，同期纳入96名健康者作为正常对照。检索既往相似遗传特征报道的原始文献，归纳其突变类型及临床特征。结果该家系成员的WES发现，FBN1基因NM_000138.4：p.Gly1754Ser/c.5260G〉A的新突变位点位于42号外显子，生物学信息预测提示其具有高致病性，符合家系共分离特征；此家系存在身材矮小、短指/趾、关节僵硬临床特征，眼部存在球形晶状体、晶状体脱位、中度近视和继发性青光眼等特征。既往共报道4个与WMS相关的FBN1突变，其中3个位于41－42外显子上，1个为跨域9－11外显子的大片段缺失，均表现为球形晶状体－身材矮小－短指/趾－关节僵硬的典型体征，此外WMS患者常见厚皮症，偶有心血管受累，少数报道腹部隆凸、脐疝等特征。结论本家系符合WMS的临床特征和遗传学诊断，本次研究中发现了位于FBN1基因的新突变位点c.5260G〉A。文献回顾分析显示FBN1基因的41－42号外显子突变是今后常染色体显性遗传WMS筛查的热点区域。

ObjectiveTo screen the disease-causing genes in an autosomal dominant（AD）Weill-Marchesani syndrome （WMS） family from Henan province in China, and to analyze the relationship between genotypes and phenotypes of the AD WMS.MethodsA family with suspected WMS was collected and studied in Henan Eye Hospital from September 2016 to July 2017.Clinical data and genomic DNA of the families were analyzed and genetic variations were screened by whole-exome sequencing （WES） The candidate genes related to ectopia lentis （FBN1, ADAMTSL2, ADAMTSL4, TGFBR2, CBS, ADAMTS10, ADAMTS17） were analyzed, and multiplex ligation dependent probe amplification （MLPA） was applied.Novel variants were further evaluated by sequencing 96 normal individuals.The previous reports with similar genetic characteristics were reviewed and the mutation types and clinical features were summarized.Written informed consent was obtained from the participants or their guardians before the collection of their venous blood and clinical data.Ethical approval was obtained from the Institutional Review Board of Henan Eye Institute.ResultsThe suspicious mutation of the c. 5260G〉A was detected in exon 42 of the FBN1 by WES in this family, which was predicted to be pathogenic and cosegregated with the disease; the clinical futures of the patients in the family included proportionate short stature, brachydactyly, joint stiffness, and the ocular problems included microspherophakia, moderate myopia, secondary glaucoma.Four mutations of FBN1 that related to WMS were reported in previous literature, and three of them were located in 41-42 exons and the others were the deletion of exons 9-11.All patients had typical clinical features of microspherophakia, short stature, brachydactyly, joint stiffness.In addition, thick skin was common, heart defects were occasional, protuberant abdomen and umbilical hernia were rarely reported.ConclusionsThe affected members in this family are in according with the clinical and genetic diagnosis of WMS.A novel mutation （c.5260G〉A） in FBN1 is discovered, which increases the spectrum of WMS mutation.The 41-42 exons of the FBN1 are hotspot of mutation in WMS.