目的:探讨中国四个家系Waardenburg综合征(WS)的遗传基础。
方法:选择2021年7月至2022年3月在郑州大学第一附属医院就诊的4名WS先证者及其谱系成员作为研究对象。Proband1,一个2岁11个月的女性,已经模糊了2年多的语言。Proband2,一个10岁的女性,有8年的双边听力损失。Proband3,28岁男性,右侧听力损失超过10年。Proband4,一个2岁的男性,左侧听力损失一年。收集四个先证者及其谱系成员的临床资料,并进行了辅助检查。从外周血样品中提取基因组DNA并进行全外显子组测序。通过Sanger测序验证候选变体。
结果:Proband1,伴有严重的双侧感音神经性听力损失,蓝色虹膜和反乌托邦角胸,被发现有一个杂合的c.667C>T(p。Arg223Ter)PAX3基因的无义变体,是从她父亲那里继承下来的.根据美国医学遗传学和基因组学学院(ACMG)的指南,该变异体被分类为致病性(PVS1+PM2_支持+PP4),先证者诊断为WSI型Proband2型,右侧中度感音神经性听力损失,左侧重度感音神经性听力损失,拥有杂合的移码c.1018_1022del(p。Val340SerfsTer60)SOX10基因的变体。她的父母都没有相同的变体。根据ACMG指南,它被归类为致病性(PVS1+PM2_支持+PP4+PM6),先证者被诊断为WSII型。Proband3,右侧有严重的感觉神经性听力损失,具有杂合c.23delC(p。Ser8TrpfsTer5)SOX10基因的移码变体。根据ACMG指南,它被归类为致病性(PVS1+PM2_支持+PP4),先证者被诊断为WSII型。Proband4,左侧有严重的感觉神经性听力损失,具有杂合c.7G>T(p。Glu3Ter)从母亲那里继承的MITF基因的无义变体。根据ACMG指南,该变异体被分类为致病性(PVS1+PM2_支持+PP4),先证者被诊断为WSII型。
结论:通过基因检测,4名先证者均被诊断为WS.上述发现促进了他们家系的分子诊断和遗传咨询。
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 type I. 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 type II. 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 type II. Proband 4, with profound sensorineural hearing loss on the left side, has harbored a heterozygous c.7G>T (p.Glu3Ter) nonsense variant of the MITF gene which was inherited from his mother. Based on the ACMG guidelines, the variant was classified as pathogenic (PVS1+PM2_Supporting+PP4), and the proband was diagnosed with WS type II.
CONCLUSIONS: By genetic testing, the four probands were all diagnosed with WS. Above finding has facilitated molecular diagnosis and genetic counseling for their pedigrees.