Objective: To analyze the clinical manifestations of a patient with branchiootic syndrome(BOS) and her families and to carry out genetic testing in order to specify the biological pathogenesis. Methods: Clinical data of the patient and her families were collected. Genomic DNA in the peripheral blood of the proband and her family members was extracted. All exons of 406 deafness-related susceptible genes as well as their flanking regions were sequenced by high-throughput sequencing, and the mutation sites of the proband and her parents were validated by Sanger sequencing. Results: There were nine members in three generations, of whom four presented with hearing loss, preauricular fistula and branchial fistula which met the diagnostic criteria of BOS. Proband and her mother presented with auricle malformation and inner ear malformation. And no one had abnormalities in the kidneys of all the patients. Pedigree analysis revealed that the mode of inheritance in the family was consistent with the autosomal dominant pattern. Mutational analysis showed that all the affected patients detected a heterozygous frameshift variation c.1255delT in the EYA1 gene, which had not been reported. Genotype and phenotype were co-isolated in this family. Such a frameshift variation produced a premature termination codon, thereby causing premature termination of translation (p.C419VFS*12). ACMG identified that the mutation was pathogenic. This mutation was novel and not detected in controls. A heterozygous missense variation mutation c.403G>A(p.G135S) in EYA1 gene was also detected in three members of this family. ACMG identified that the mutation clinical significance was uncertain. However, two of whom were normal, which seemed the disease was not caused by this mutation in this family. Conclusions: A novel frameshift mutation in EYA1(c.1255delT) is the main molecular etiology of BOS in the Chinese family. This study expands the mutational spectrum of EYA1 gene. The clinical manifestations are heterogeneous among patients in this family. The diagnosis of BOS should combine gene tests with clinical phenotypes analysis.
目的： 通过分析鳃耳综合征患儿及家系成员的临床表现和基因序列，明确其生物学致病原因。 方法： 收集我国云南地区1例鳃耳综合征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，对406个耳聋相关易感基因全部外显子及其侧翼序列进行高通量测序，并对突变位点进行Sanger测序验证分析。 结果： 该家系包括3代9人，其中4人表现为听力下降、耳前瘘管和鳃裂瘘，符合鳃耳综合征的临床诊断。先证者及其母亲耳廓畸形，内耳发育畸形，肾脏未见异常。系谱分析显示，该家系遗传方式为常染色体显性遗传。基因检测显示在所有发病成员的EYA1基因上均发现一个未见报道的杂合突变位点，c.1255delT（p.C419Vfs*12），家系内该变异与耳聋表型共分离，且此突变为移码突变，导致终止密码子提前出现。根据美国医学遗传学与基因组学学会（American College of Medical Genetics and Genomics，ACMG）指南初步判定为致病性变异，家系中表型正常成员及100名健康人中均未发现该位点突变。家系中3名成员存在EYA1 c.403G>A（p.G135S）杂合突变，该突变导致第135号氨基酸由甘氨酸变异为丝氨酸，为错义突变，其中2名成员表型正常，ACMG指南判定该变异临床意义未明。 结论： EYA1 c.1255delT是该家系鳃耳综合征患者的主要分子病因，家系内患病个体间临床表现具有异质性，鳃耳综合征的诊断需将表型和基因测序密切结合。.