Table1_Non-syndromic enlarged vestibular aqueduct caused by novel compound mutations of the SLC26A4 gene: a case report and literature review.docx

Enlarged vestibular aqueduct is an autosomal genetic disease mainly caused by mutations in the SLC26A4 gene and includes non-syndromic and syndromic types. This study aimed to identify genetic defects in a Chinese patient with non-syndromic enlarged vestibular aqueduct (NSEVA) and to investigate the impact of variants on the severity of non-syndromic enlarged vestibular aqueduct. A male patient with NSEVA, aged approximately 6 years, was recruited for this study. The clinical characteristics and results of auxiliary examinations, including laboratory and imaging examinations, were collected, and 127 common hereditary deafness genes were detected by chip capture high-throughput sequencing. Protein structure predictions, the potential impact of mutations, and multiple sequence alignments were analyzed in silico. Compound heterozygote mutations c.1523_1528delinsAC (p.Thr508Asnfs*3) and c.422T>C (p.Phe141Ser) in the SLC26A4 gene were identified. The novel frameshift mutation c.1523_1528delinsAC produces a severely truncated pendrin protein, and c.422T>C has been suggested to be a disease-causing mutation. Therefore, this study demonstrates that the novel mutation c.1523_1528delinsAC in compound heterozygosity with c.422T>C in the SLC26A4 gene is likely to be the cause of NSEVA. Cochlear implants are the preferred treatment modality for patients with NSEVA and severe-to-profound sensorineural hearing loss Genetic counseling and prenatal diagnosis are essential for early diagnosis. These findings expand the mutational spectrum of SLC26A4 and improve our understanding of the molecular mechanisms underlying NSEVA.

大前庭导水管综合征（Enlarged vestibular aqueduct）是一种常染色体遗传性疾病，主要由SLC26A4基因（SLC26A4 gene）突变引发，可分为非综合征型和综合征型。本研究旨在明确1例中国非综合征型大前庭导水管综合征（non-syndromic enlarged vestibular aqueduct, NSEVA）患者的遗传缺陷，并探究变异对非综合征型大前庭导水管综合征病情严重程度的影响。本研究纳入1例约6岁的男性非综合征型大前庭导水管综合征患者，收集其临床特征及实验室、影像学等辅助检查结果，采用芯片捕获高通量测序（chip capture high-throughput sequencing）技术对127种常见遗传性耳聋基因（common hereditary deafness genes）进行检测，并通过生物信息学分析对蛋白结构预测、突变的潜在影响及多序列比对进行了探究。最终检出SLC26A4基因的复合杂合突变c.1523_1528delinsAC（p.Thr508Asnfs*3）与c.422T>C（p.Phe141Ser）。其中新型移码突变c.1523_1528delinsAC可导致潘德林蛋白（pendrin）发生严重截短，而c.422T>C已被证实为致病突变。因此，本研究证实，SLC26A4基因中新型突变c.1523_1528delinsAC与c.422T>C形成的复合杂合状态，极有可能是非综合征型大前庭导水管综合征的致病原因。人工耳蜗植入（cochlear implants）是伴重度至极重度感音神经性耳聋（sensorineural hearing loss）的非综合征型大前庭导水管综合征患者的首选治疗方案。遗传咨询与产前诊断对于该疾病的早期诊断至关重要。本研究结果拓展了SLC26A4基因的突变谱，并加深了我们对非综合征型大前庭导水管综合征分子致病机制的理解。