Wang Lulu, Mao Lu, Xu Hongen, Sun Shuping, Zuo Bin, Lu Wei
Department of Otorhinolaryngology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2023 Jun 10;40(6):661-667. doi: 10.3760/cma.j.cn511374-20220727-00498.
To explore the genetic basis for four Chinese pedigrees affected with Waardenburg syndrome (WS).
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.
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.
By genetic testing, the four probands were all diagnosed with WS. Above finding has facilitated molecular diagnosis and genetic counseling for their pedigrees.
探究四个患瓦登伯革综合征（WS）的中国家系的遗传基础。
选取2021年7月至2022年3月期间在郑州大学第一附属医院就诊的四名WS先证者及其家系成员作为研究对象。先证者1为一名2岁11个月的女性，言语模糊超过2年。先证者2为一名10岁女性，双侧听力丧失8年。先证者3为一名28岁男性，右侧听力丧失超过10年。先证者4为一名2岁男性，左侧听力丧失1年。收集四名先证者及其家系成员的临床资料，并进行辅助检查。从外周血样本中提取基因组DNA，进行全外显子组测序。候选变异通过桑格测序进行验证。
先证者1患有严重的双侧感音神经性听力丧失、蓝色虹膜和内眦异位，被发现携带PAX3基因的杂合c.667C>T（p.Arg223Ter）无义变异，该变异遗传自她的父亲。根据美国医学遗传学与基因组学学会（ACMG）的指南，该变异被分类为致病性变异（PVS1+PM2_Supporting+PP4），先证者被诊断为I型WS。先证者2右侧中度感音神经性听力丧失，左侧重度感音神经性听力丧失，携带SOX10基因的杂合移码c.1018_1022del（p.Val340SerfsTer60）变异。她的父母均未携带相同变异。根据ACMG指南，该变异被分类为致病性变异（PVS1+PM2_Supporting+PP4+PM6），先证者被诊断为II型WS。先证者3右侧严重感音神经性听力丧失，携带SOX10基因的杂合c.23delC（p.Ser8TrpfsTer5）移码变异。根据ACMG指南，该变异被分类为致病性变异（PVS1+PM2_Supporting+PP4），先证者被诊断为II型WS。先证者4左侧严重感音神经性听力丧失，携带MITF基因的杂合c.7G>T（p.Glu3Ter）无义变异，该变异遗传自他的母亲。根据ACMG指南，该变异被分类为致病性变异（PVS1+PM2_Supporting+PP4），先证者被诊断为II型WS。
通过基因检测，四名先证者均被诊断为WS。上述发现有助于对其家系进行分子诊断和遗传咨询。
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