FBN1基因变异患者4例的临床表现及遗传学分析

Clinical manifestations and genetic analysis of four patients with variants of FBN1 gene

目的探讨4例疑似马凡综合征(MFS)患者的遗传学病因。方法选取2019年9月12日至2021年3月27日就诊于四川大学华西第二医院的4例疑似MFS的男性患者及其家系成员作为研究对象。采集患者及其亲属的外周静脉血样,提取基因组DNA,对其进行家系全外显子组测序,并用Sanger测序对候选变异进行验证。根据美国医学遗传学与基因组学学会(ACMG)变异相关指南判定变异的致病性。结果全外显子组测序结果提示4例患者FBN1基因分别存在第5外显子c.430_433del(p.His144fs)缺失变异、第6外显子c.493C>T(p.Arg165*)无义变异、第44外显子c.5304_5306del(p.Asp1768del)缺失变异以及第42外显子c.5165C>G(p.Ser1722Cys)错义变异。根据ACMG变异相关指南,c.430_433del和c.493C>T变异评级为致病性变异(PVS1+PM2_Supporting+PP4;PVS1+PS1+PS2+PM2_Supporting+PP4)。c.5304_5306del和c.5165C>G变异评级为可能致病性变异(PS2+PM2_Supporting+PM4+PP4;PS2_Moderate+PS1+PM1+PM2_Supporting)。结论FBN1基因的c.430_433del、c.5304_5306del既往未见报道,上述结果丰富了MFS的基因变异谱,为患者的遗传咨询和产前诊断提供了依据。

Objective To explore the genetic basis for four patients suspected for Marfan syndrome(MFS).Methods Four male patients with suspected MFS and their family members who were treated at West China Second Hospital of Sichuan University from September 12,2019 to March 27,2021 were selected as the study subjects.Peripheral venous blood samples were collected from the patients and their parents or other pedigree members for the extraction of genomic DNA.Whole exome sequencing was carried out,and candidate variants were validated by Sanger sequencing.The pathogenicity of the variants was determined based on the guidelines from the American College of Medical Genetics and Genomics(ACMG).Results Genetic testing revealed that all four patients had harbored variants of the FBN1 gene,including c.430_433del(p.His144fs)deletional variant in exon 5,c.493C>T(p.Arg165*)nonsense variant in exon 6,c.5304_5306del(p.Asp1768del)deletional variant in exon 44 and c.5165C>G(p.Ser1722Cys)missense variant in exon 42.According to the ACMG guidelines,the c.430_433del and c.493C>T were classified as pathogenic variants(PVS1+PM2_Supporting+PP4;PVS1+PS1+PS2+PM2_Supporting+PP4).c.5304_5306del and c.5165C>G were classified as likely pathogenic variants(PS2+PM2_Supporting+PM4+PP4;PS2_Moderate+PS1+PM1+PM2_Supporting).Conclusion The c.430_433del and c.5304_5306del variants of the FBN1 gene identified in this study were unreported previously.Above results have enriched the variation spectrum of the FBN1 gene and provided a basis for genetic counseling and prenatal diagnosis of patients with MFS and acromicric dysplasia.