机构地区:[1]郑州大学第一附属医院耳鼻咽喉科,郑州450052 [2]郑州大学医学科学院精准医学中心,郑州450052
出 处:《中华医学遗传学杂志》2023年第6期661-667,共7页Chinese Journal of Medical Genetics
摘 要:目的探讨4例Waardenburg综合征(WS)先证者的致病原因。方法选取2021年7月至2022年3月就诊于郑州大学第一附属医院的4例WS先证者及其家系为研究对象。先证者1为2岁11月龄女性患儿,于2021年11月3日因"言语不清2+年"就诊;先证者2为10岁女性患儿,于2021年7月13日因"双耳听力差8年"就诊;先证者3为28岁男性患者,于2022年3月23日因"右耳听力下降10+年"就诊;先证者4为2岁龄男性患儿,于2022年3月9日因"左耳听力差1年"就诊。收集先证者及其家系成员的病史资料,并进行听力学检查和颞部CT检查。提取先证者及其家系成员血样基因组DNA进行全外显子组测序,并进行Sanger测序验证。结果先证者1表现为双耳极重度感音神经性耳聋、双眼蓝色虹膜及内眦外移,存在父源PAX3:c.667C>T(p.Arg223 Ter)无义杂合变异。根据美国医学遗传学与基因组学学会(ACMG)的变异评级指南,该变异评级为致病性变异(PVS1+PM2_Supporting+PP4),先证者1确诊为WSⅠ型。先证者2表现为右耳中度感音神经性耳聋、左耳极重度感音神经性耳聋、双眼蓝色虹膜及内耳发育畸形,存在SOX10:c.1018_1022del(p.Val340Serfs Ter60)移码杂合变异,先证者2的父母此位点为野生型,考虑为新发变异。根据ACMG的变异评级指南,SOX10:c.1018_1022del变异评级为致病性变异(PVS1+PM2_Supporting+PP4+PM6),先证者2确诊为WSⅡ型。先证者3表现为右耳极重度感音神经性耳聋、左耳听力未见异常。存在SOX10:c.23delC(p.Ser8TrpfsTer5)移码杂合变异,变异来源未知。根据ACMG的变异评级指南,SOX10:c.23delC变异评级为致病性变异(PVS1+PM2_Supporting+PP4),先证者3确诊为WSⅡ型。先证者4表现为左耳极重度感音神经性耳聋、右耳听力未见异常,存在母源性MITF:c.7G>T(p.Glu3 Ter)无义杂合变异。根据ACMG的变异评级指南,MITF:c.7G>T变异评级为致病性变异(PVS1+PM2_Supporting+PP4),先证者4确诊为WSⅡ型。结论本研究通过�Objective To explore the genetic basis for four Chinese pedigrees affected with Waardenburg syndrome(WS).Methods Four WS probands and their pedigree members who had presented at the First Affiliated Hospital of Zhengzhou University between July 2021 and March 2022 were selected as the study subjects.Proband 1,a 2-year-and-11-month female,had blurred speech for over 2 years.Proband 2,a 10-year-old female,had bilateral hearing loss for 8 years.Proband 3,a 28-year-old male,had right side hearing loss for over 10 years.Proband 4,a 2-year-old male,had left side hearing loss for one year.Clinical data of the four probands and their pedigree members were collected,and auxiliary examinations were carried out.Genomic DNA was extracted from peripheral blood samples and subjected to whole exome sequencing.Candidate variants were verified by Sanger sequencing.Results Proband 1,with profound bilateral sensorineural hearing loss,blue iris and dystopia canthorum,was found to have harbored a heterozygous c.667C>T(p.Arg223Ter)nonsense variant of the PAX3 gene,which was inherited from her father.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the variant was classified as pathogenic(PVS1+PM2_Supporting+PP4),and the proband was diagnosed with WS typeⅠ.Proband 2,with moderate sensorineural hearing loss on the right side and severe sensorineural hearing loss on the left side,has harbored a heterozygous frameshifting c.1018_1022del(p.Val340SerfsTer60)variant of the SOX10 gene.Neither of her parents has harbored the same variant.Based on the ACMG guidelines,it was classified as pathogenic(PVS1+PM2_Supporting+PP4+PM6),and the proband was diagnosed with WS typeⅡ.Proband 3,with profound sensorineural hearing loss on the right side,has harbored a heterozygous c.23delC(p.Ser8TrpfsTer5)frameshifting variant of the SOX10 gene.Based on the ACMG guidelines,it was classified as pathogenic(PVS1+PM2_Supporting+PP4),and the proband was diagnosed with WS typeⅡ.Proband 4,with profound sensorineural heari
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