5个鳃耳(肾)综合征家系的致病突变和诊疗分析

Branchio-oto-renal syndrome or branchio-oto syndrome:the clinical and genetic analysis in five Chinese families

目的筛查5个鳃耳(肾)综合征家系的致病基因,探讨其表型特征和临床诊疗情况。方法招募2018年12月至2021年9月经临床诊断为鳃耳(肾)综合征的5个家系,收集家族史和病史信息,绘制家系图。对先证者及家系成员进行听力学、颞骨影像学及肾脏学检查。获取外周血提取DNA,利用二代高通量测序技术筛查鳃耳(肾)综合征分子病因。对确诊患者建议并实施相应临床干预。结果5个家系共8人被诊断为鳃耳(肾)综合征。8例患者均存在听力损失、耳前瘘管和不同程度耳畸形,4例患有鳃裂瘘管或囊肿。除2例未明确肾脏表型,余6例经肾脏B超或CT检查未发现肾脏异常。基因检测确定4个致病或可能致病的EYA1基因变异(NM000503.6:c.1715G>T;c.1140+1G>A;c.639G>C;c.1475+1G>C),其中c.1715G>T变异为首次报道。3例患者行听骨链重建术后,听力无明显改善,其中2例验配助听器或植入人工耳蜗而获得满意的听力康复效果。结论二代高通量测序技术可辅助鳃耳(肾)综合征的诊断和遗传咨询。听力损失、耳前瘘管、耳畸形和鳃裂瘘管或囊肿是本研究鳃耳(肾)综合征患者的常见表型。鼓室探查听骨链重建对改善鳃耳(肾)综合征患者听力损失可能存在一定局限性,助听器和人工耳蜗植入可以帮助其实现听力康复。

Objective To screen the causative genes of five families with branchio-oto-renal syndrome(BORS)or branchio-oto syndrome(BOS)and to analyze the phenotypic characteristics and clinical management strategies of patients.Methods Five families with BORS/BOR from December 2018 to September 2021 were recruited,information of patients,including family history and medical history,was collected,and genealogies were drawn.The examinations concerning audiology,nephrology,and radiology were performed on the affected individuals.Peripheral blood was obtained for DNA extraction,then next-generation sequencing technology was used to screen candidate variants associated with BORS/BOS.Based on patient′s clinical results,the appropriate interventions were recommended and implemented.Results Eight individuals were diagnosed with BOS or BORS.Of the eight patients,all had hearing loss,preauricular pits and ear malformations,and only four presented with branchial cleft fistulae or cysts.Except for two patients(5-I-2,5-II-2)who did not undergo renal examination,the remaining six lacked renal abnormalities.Genetic analysis identified four likely pathogenic or pathogenic EYA1 variants(c.1715G>T,c.1140+1G>A,c.639G>C,c.1475+1G>C;NM_000503.6),and c.1715G>T was first reported in this study.Middle ear ossicular reconstruction was performed in 1-II-2,2-I-2 and 3-II-2,but did not yield the expected results;then hearing aids and cochlear implantation were recommended and achieved satisfactory results.Conclusions Next-generation sequencing technology facilitates the diagnosis and genetic counseling of BORS/BOS.Hearing loss,preauricular pits,ear malformations and branchial cleft fistulae or cysts are the most common manifestations of patients in this study.Middle ear surgeries for improving hearing loss may have some limitations in BORS/BOS patients,and hearing aids and cochlear implantation can contribute to hearing gains.