Supplementary Material for: Novel <b><i>TECTA </i></b>Mutations Identified in Stable Sensorineural Hearing Loss and Their Clinical Implications

TECTA is a causative gene of autosomal dominant (DFNA8/A12) and autosomal recessive (DFNB 21) nonsyndromic sensorineural hearing loss (NSHL). Mutations in TECTA account for 4% of all autosomal dominant NSHL cases in some populations and are thus thought to be one of the major causes of autosomal dominant NSHL. A genotype-phenotype correlation for autosomal dominant mutations in the TECTA gene has been proposed. Two families (SB146 and SB149), which segregated moderate NSHL in an autosomal dominant fashion, were included in this study. We performed targeted resequencing of 134 known deafness genes (TRS-134) and bioinformatics analyses to find causative mutations for NSHL in these 2 families. Through TRS-134, we detected 2 novel mutations, i.e. c.3995G>T (p.C1332F) and c.5618C>T (p.T1873I), in the TECTA gene. These mutations cosegregated with NSHL in the studied families and were not detected in normal controls. The mutations c.3995G>T and c.5618C>T reside in the von Willebrand factor type D3-D4 (vWFD3-D4) interdomain of the zonadhesin (ZA) domain and the zona pellucida (ZP) domain, respectively. p.C1332F is the first mutation detected in the vWFD3-D4 interdomain of the ZA domain. The mutations p.C1332F and p.T1873I were associated with stable high-frequency and mid-frequency hearing loss, respectively. Notably, the cysteine residue mutated to phenylalanine in SB146 was not related to progression of sensorineural hearing loss, which argues against the previous hypothesis. Here we confirm a known genotype-phenotype correlation for the ZP domain and propose a hypothetical genotype-phenotype correlation which relates mutations in vWFD3-D4 to stable high-frequency NSHL in Koreans. This clinical feature makes subjects with the missense mutation in the vWFD3-D4 interdomain of TECTA potentially good candidates for middle ear implantation. i 2014 S. Karger AG, BaselTECTA基因是常染色体显性（DFNA8/A12）与常染色体隐性（DFNB21）非综合征性感音神经性听力损失（NSHL）的致病基因。在部分人群中，TECTA基因突变占所有常染色体显性NSHL病例的4%，因此被认为是常染色体显性NSHL的主要致病原因之一。已有研究提出TECTA基因常染色体显性突变存在基因型-表型关联。本研究纳入两个以常染色体显性方式遗传中度NSHL的家系（SB146与SB149），针对这两个家系开展了134个已知耳聋基因的靶向重测序（TRS-134）以及生物信息学分析，以寻找NSHL的致病突变。通过TRS-134检测，我们在TECTA基因中发现了两个全新突变：c.3995G>T（p.C1332F）与c.5618C>T（p.T1873I）。上述突变在受试家系中与NSHL共分离，且在正常对照人群中未被检出。突变c.3995G>T与c.5618C>T分别位于zonadhesin（ZA）结构域的血管性血友病因子D3-D4型（vWFD3-D4）域间连接区，以及透明带（ZP）结构域中。p.C1332F是首个在ZA结构域的vWFD3-D4域间连接区中检出的突变。突变p.C1332F与p.T1873I分别与稳定的高频听力损失以及中频听力损失相关。值得注意的是，SB146家系中突变为苯丙氨酸的半胱氨酸残基与感音神经性听力损失的进展并无关联，这一结果与既往假说相悖。本研究证实了ZP结构域已被报道的基因型-表型关联，并提出了一项假想的基因型-表型关联：即vWFD3-D4区域的突变与韩国人群中稳定的高频NSHL相关。这一临床特征使得携带TECTA基因vWFD3-D4域间连接区错义突变的受试者，有望成为中耳植入术的优质候选人群。©2014 S. Karger AG，巴塞尔