Next-generation sequencing-based mutation analysis of genes associated with enlarged vestibular aqueduct in Chinese fami
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OTOLOGY
Next‑generation sequencing‑based mutation analysis of genes associated with enlarged vestibular aqueduct in Chinese families Yalan Liu1,2 · Jie Wen1,2 · Shushan Sang1,2 · Lingyun Mei1,2 · Chufeng He1,2 · Lu Jiang1,2 · Sida Huang1,2 · Yong Feng1,2 Received: 15 February 2020 / Accepted: 11 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Objectives The identification of gene mutations enables more appropriate genetic counseling and proper medical management for EVA patients. The purpose of this study was to validate the accuracy and sensitivity of our method for comprehensive mutation detection in EVA, and summarize these data to explore a more accurate and convenient genetic diagnosis method. Methods A multiplex PCR sequencing panel was designed to capture the exons of three known EVA-associated genes (SLC26A4, KCNJ10, and FOXI1), and NGS was conducted in 17 Chinese families with EVA. Results A total of 16 SLC26A4 variants were found in 21 probands with bilateral EVA, including three novel variants (c.416G>A, c.823G>A and c.1027G>C), which were not reported in the dbSNP, gnomAD database, and ClinVar databases. One patient carried a FOXI1 variant (heterozygous, c.214C>A) and one patient carried a KCNJ10 variant (heterozygous, c.1054C>A), both of which were novel variants. Biallelic potential pathogenic variants were detected in 21/21patient samples, leading to a purported diagnostic rate of 100%. All results were verified by Sanger sequencing. Conclusion This result supplemented the mutation spectrum of EVA, and supports that combined multiple PCR-targeted enrichment, and NGS is a valuable molecular diagnostic tool for EVA, and is suitable for clinical application. Keywords EVA · Hearing loss · Next-generation sequencing · Genetic mutations
Introduction Enlarged vestibular aqueduct (EVA) is one of the most common inner ear malformations, often identified by a computed tomography (CT) scan in subjects with sensorineural hearing loss. EVA is recognized as the most penetrant feature of Pendred syndrome and identified in patients with nonsyndromic hearing loss with EVA (NSEVA). EVA has also been detected in a subset of patients with branchiooto-renal (BOR) syndrome, Andermann syndrome, heart abnormalities, and deafness associated with the recessive form of distal renal tubular acidosis [1]. However, there is * Yong Feng [email protected] 1
Department of Otolaryngology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha 410008, Hunan, China
Province Key Laboratory of Otolaryngology Critical Diseases, Changsha 410008, Hunan, China
2
no reported evidence that mutations of the genes underlying these syndromes cause NSEVA. Mutations in the SLC26A4 (DFNB4; MIM 605646) gene are known to be responsible for both typical Pendred syndrome and NSEVA [2]. 4208 variants have been identified in SLC26A4 (https://deafn essvar iatio ndata base. org/gene_page/SLC26A 4, REF:PMID: 30245029). Of these variants, 419 are classified as pathogenic (P), 45 a
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