Abstract：
OBJECTIVE: To explore the genetic basis for a Chinese pedigree affected with Branchio-Oto syndrome (BOS).
METHODS: A pedigree with BOS which had presented at the Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Clinical data of the pedigree was collected. Peripheral blood samples of the proband and her parents were collected. Whole exome sequencing (WES) was carried out for the proband. Multiplex ligation-dependent probe amplification (MLPA) was used to verify the result of WES, short tandem repeat (STR) analysis was used to verify the relationship between the proband and her parents, and the pathogenicity of the candidate variant was analyzed.
RESULTS: The proband, a 6-year-old girl, had manifested severe congenital deafness, along with inner ear malformation and bilateral branchial fistulae. WES revealed that she has harbored a heterozygous deletion of 2 466 kb at chromosome 8q13.3, which encompassed the EYA1 gene. MLPA confirmed that all of the 18 exons of the EYA1 gene were lost, and neither of her parents has carried the same deletion variant. STR analysis supported that both of her parents are biological parents. Based on the guidelines from the American College of Medical Genetics and Genomics, the deletion was classified as pathogenic (PVS1+PS2+PM2_Supporting+PP4).
CONCLUSIONS: The heterozygous deletion of EYA1 gene probably underlay the pathogenicity of BOS in the proband, which has provided a basis for the clinical diagnosis.
METHODS: A pedigree with BOS which had presented at the Genetics and Prenatal Diagnosis Center of the First Affiliated Hospital of Zhengzhou University in May 2021 was selected as the study subject. Clinical data of the pedigree was collected. Peripheral blood samples of the proband and her parents were collected. Whole exome sequencing (WES) was carried out for the proband. Multiplex ligation-dependent probe amplification (MLPA) was used to verify the result of WES, short tandem repeat (STR) analysis was used to verify the relationship between the proband and her parents, and the pathogenicity of the candidate variant was analyzed.
RESULTS: The proband, a 6-year-old girl, had manifested severe congenital deafness, along with inner ear malformation and bilateral branchial fistulae. WES revealed that she has harbored a heterozygous deletion of 2 466 kb at chromosome 8q13.3, which encompassed the EYA1 gene. MLPA confirmed that all of the 18 exons of the EYA1 gene were lost, and neither of her parents has carried the same deletion variant. STR analysis supported that both of her parents are biological parents. Based on the guidelines from the American College of Medical Genetics and Genomics, the deletion was classified as pathogenic (PVS1+PS2+PM2_Supporting+PP4).
CONCLUSIONS: The heterozygous deletion of EYA1 gene probably underlay the pathogenicity of BOS in the proband, which has provided a basis for the clinical diagnosis.
摘要：
目的：探讨一个Branchio-Oto综合征（BOS）中国家系的遗传基础。
方法：选取2021年5月在郑州大学第一附属医院遗传与产前诊断中心就诊的BOS系作为研究对象。收集谱系的临床数据。收集先证者及其父母的外周血样本。对先证者进行全外显子组测序(WES)。多重连接依赖性探针扩增(MLPA)用于验证WES的结果,短串联重复(STR)分析用于验证先证者与父母之间的关系,并对候选变异体的致病性进行了分析。
结果：先证者，一个6岁的女孩,表现为严重的先天性耳聋，伴有内耳畸形和双侧分支瘘。WES透露，她在8q13.3号染色体上有2466kb的杂合缺失，其中包括EYA1基因。MLPA证实EYA1基因的18个外显子全部丢失，她的父母都没有携带相同的删除变体。STR分析支持她的父母都是亲生父母。根据美国医学遗传学和基因组学学院的指南，缺失被分类为致病性(PVS1+PS2+PM2_支持+PP4)。
结论：EYA1基因的杂合缺失可能是先证者BOS致病性的基础，为临床诊断提供了依据。
方法：选取2021年5月在郑州大学第一附属医院遗传与产前诊断中心就诊的BOS系作为研究对象。收集谱系的临床数据。收集先证者及其父母的外周血样本。对先证者进行全外显子组测序(WES)。多重连接依赖性探针扩增(MLPA)用于验证WES的结果,短串联重复(STR)分析用于验证先证者与父母之间的关系,并对候选变异体的致病性进行了分析。
结果：先证者，一个6岁的女孩,表现为严重的先天性耳聋，伴有内耳畸形和双侧分支瘘。WES透露，她在8q13.3号染色体上有2466kb的杂合缺失，其中包括EYA1基因。MLPA证实EYA1基因的18个外显子全部丢失，她的父母都没有携带相同的删除变体。STR分析支持她的父母都是亲生父母。根据美国医学遗传学和基因组学学院的指南，缺失被分类为致病性(PVS1+PS2+PM2_支持+PP4)。
结论：EYA1基因的杂合缺失可能是先证者BOS致病性的基础，为临床诊断提供了依据。
