新发EYA1基因杂合缺失变异所致鳃-耳综合征型耳聋一个家系的遗传学诊断

Genetic diagnosis of a Branchio-Oto syndrome pedigree due to a de novo heterozygous deletion of EYA1 gene

目的探究1个鳃-耳综合征(BOS)型耳聋家系的基因变异类型,明确可能遗传学病因。方法选取2021年5月于郑州大学第一附属医院遗传与产前诊断中心就诊的1个BOS型耳聋家系为研究对象。采集本研究BOS型耳聋家系的临床资料,抽取先证者及其父母的外周血样,提取基因组DNA。应用全外显子组测序(WES)对先证者进行基因检测,应用多重连接探针扩增(MLPA)对测序结果进行家系验证,应用短串联重复序列(STR)分析技术对先证者及其父母进行亲缘关系鉴定,对候选变异进行致病性分析。结果先证者为6岁女性,临床主要表现为内耳畸形合并双侧鳃裂瘘管的先天性重度耳聋。WES检测发现先证者第8号染色体q13.3处存在2466 kb的杂合缺失,该区域覆盖EYA1基因。MLPA检测证实先证者EYA1基因的全部18个外显子均存在杂合缺失,其父母未携带该基因缺失变异,提示为新发变异。STR分析支持先证者与其父母的生物学亲缘关系。根据美国医学遗传学与基因组学学会(ACMG)与ClinGen联合制订的相关指南,该变异被评级为致病性变异(PVS1+PS2+PM2_Supporting+PP4)。结论EYA1基因杂合缺失变异可能是本研究BOS型耳聋家系的遗传学病因,为临床诊断该家系提供参考依据。

ObjectiveTo explore the genetic basis for a Chinese pedigree affected with Branchio-Oto syndrome(BOS).MethodsA 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.ResultsThe 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 2466 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).ConclusionThe heterozygous deletion of EYA1 gene probably underlay the pathogenicity of BOS in the proband,which has provided a basis for the clinical diagnosis.