EYA1基因变异的综合征家系临床表型和基因分析

Clinical phenotypic and genetic analysis of syndrome families with EYA1 gene variants

目的:研究一个鳃耳综合征(branchio-oto syndrome)家系临床表型,探寻该家系的遗传学病因。方法:收集1例诊为鳃耳综合征的患儿及家系成员的临床资料,提取先证者及其家系成员的外周血基因组DNA,进行全外显子组测序,并对突变位点进行Sanger测序验证分析。结果:该家系包括2代4人,其中3人有表型,2人听力下降,并且有双侧耳前瘘管,双侧鳃裂瘘,1人双侧耳前瘘,双侧鳃裂瘘,均符合鳃耳综合征的临床诊断,该家系遗传方式为常染色体显性遗传,基因检测显示该家系所有发病成员EYA1基因均有c.1744delC(p.L592Cfs*47)变异,表型正常成员该位点为野生型,家系内符合基因型与表型共分离。该突变为移码突变,导致终止密码子提前出现,该突变目前尚未见报道。根据美国医学遗传学与基因组学学会指南,该变异初步判定为疑似致病性变异。结论:该家系新发现的EYA1c.1744delC(p.L592Cfs*47)突变为该家系患者的致病突变基因,进一步拓展了EYA1基因的突变谱,使我们对于该病有了更新的认识,为临床诊断和遗传咨询提供了重要参考。

Objective To investigate the clinical phenotype of a family with branchio-oto syndrome(BOS)and to explore the genetic etiology of the syndrome in this family.Methods Clinical data were collected from a child diagnosed with BOS and his family members.Genomic DNA was extracted from peripheral blood of the proband and his family members.Whole-exome sequencing was performed,and the mutation sites were verified and analyzed by Sanger sequencing.Results The family consists of two generations with four members,three of whom exhibit the phenotype.Two members have hearing loss and bilateral preauricular fistulas and bilateral branchial cleft fistulas.One member has bilateral preauricular fistulas and bilateral branchial cleft fistulas.All of which were in line with the clinical diagnosis of gill ear syndrome,the inheritance mode of the family was autosomal dominant inheritance,genetic testing showed that all members of the family had c.1744delC(p.L592Cfs*47)mutation in the EYA1 gene,while unaffected members have the wild-type allele at this locus.This mutation is a frameshift mutation,which results in the early appearance of the stop codon,and has not been reported so far.According to ACMG guidelines,the variant was preliminarily determined to be suspected pathogenic.Conclusion The newly discovered EYA1c.1744delC(p.L592Cfs*47)mutation in this family is the pathogenic mutant gene of the patients in this family,which further expands the mutation spectrum of EYA1 gene,gives us a new understanding of the disease,and provides an important reference for clinical diagnosis and genetic counseling.