目标:Branchio-oto-renicalsyndrome(BOR,OMIM#113,650)是一种罕见的常染色体显性疾病,表现为多种症状,包括听力损失(感音神经性,导电,或混合),影响外部的结构异常,中间,和内耳,分支瘘或囊肿,以及肾脏异常。本研究旨在通过对具有Branchio-oto-renal/Branchio-tic(BO,OMIM#602,588)使用全外显子组测序的综合征,并探讨可能的致病机制。
方法:该家族跨越4代,由9个人组成,其中4例受到BOR/BO综合征的影响。表型信息,包括耳朵畸形和branch裂,是从家庭成员那里收集的。听力学,颞骨成像,并进行了肾脏超声检查。通过小基因实验进行全外显子组测序以鉴定候选致病变异并探索BOR/BO综合征的潜在分子病因。
结果:在该家族的BOR/BO综合征的临床表型中观察到家族内变异性。听力损失的严重程度和性质因家庭成员而异,混合性或感音神经性听力损失。先证者,特别是,左侧有严重的感觉神经性听力损失,右侧有中度传导性听力损失。此外,先证者表现出发育迟缓,她的母亲在怀孕期间经历了肾功能衰竭,并提前终止了妊娠。遗传测试揭示了受影响家族成员中EYA1基因中的一种新的杂合变体NM_000503.6:c.6393A>C。体外小基因实验证明了其对剪接的影响。根据美国医学遗传学学院(ACMG)的指南,该变异体被分类为可能致病.
结论:这项研究强调了同一家族内的表型异质性,报告一名育龄期女性BOR综合征患者肾功能衰竭的发生和不良妊娠结局,并丰富了EYA1基因致病变异的突变谱。
OBJECTIVE: Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural, conductive, or mixed), structural abnormalities affecting the outer, middle, and inner ear, branchial fistulas or cysts, as well as renal abnormalities.This study aims to identify the pathogenic variants by performing genetic testing on a family with Branchio-oto-renal /Branchio-otic (BO, OMIM#602,588) syndrome using whole-exome sequencing, and to explore possible pathogenic mechanisms.
METHODS: The family spans 4 generations and consists of 9 individuals, including 4 affected by the BOR/BO syndrome. Phenotypic information, including ear malformation and branchial cleft, was collected from family members. Audiological, temporal bone imaging, and renal ultrasound examinations were also performed. Whole-exome sequencing was conducted to identify candidate pathogenic variants and explore the underlying molecular etiology of BOR/BO syndrome by minigene experiments.
RESULTS: Intra-familial variability was observed in the clinical phenotypes of BOR/BO syndrome in this family. The severity and nature of hearing loss varied in family members, with mixed or sensorineural hearing loss. The proband, in particular, had profound sensorineural hearing loss on the left and moderate conductive hearing loss on the right. Additionally, the proband exhibited developmental delay, and her mother experienced renal failure during pregnancy and terminated the pregnancy prematurely. Genetic testing revealed a novel heterozygous variant NM_000503.6: c.639 + 3 A > C in the EYA1 gene in affected family members. In vitro minigene experiments demonstrated its effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was classified as likely pathogenic.
CONCLUSIONS: This study highlights the phenotypic heterogeneity within the same family, reports the occurrence of renal failure and adverse pregnancy outcomes in a female patient at reproductive age with BOR syndrome, and enriches the mutational spectrum of pathogenic variants in the EYA1 gene.