A novel frameshift mutation of SMPX causes a rare form of X-linked nonsyndromic hearing loss in a Chinese family

X-linked hearing impairment is the rarest form of genetic hearing loss (HL) and represents only a minor fraction of all cases. The aim of this study was to investigate the cause of X-linked inherited sensorineural HL in a four-generation Chinese family. A novel duplication variant (c.217dupA, p.Ile73Asnfs*5) in SMPX was identified by whole-exome sequencing. The frameshift mutation predicted to result in the premature truncation of the SMPX protein was co-segregated with the HL phenotype and was absent in 295 normal controls. Subpopulation screening of the coding exons and flanking introns of SMPX was further performed for 338 Chinese patients with nonsydromic HL by Sanger sequencing, and another two potential causative substitutions (c.238C>A and c.55A>G) in SMPX were identified in additional sporadic cases of congenital deafness. Collectively, this study is the first to report the role of SMPX in Chinese population and identify a novel frameshift mutation in SMPX that causes not only nonsyndromic late-onset progressive HL, but also congenital hearing impairment. Our findings extend the mutation and phenotypic spectrum of the SMPX gene.X连锁听力障碍（X-linked hearing impairment）是最为罕见的遗传性听力损失（HL）类型，仅占所有听力损失病例的极小一部分。本研究旨在探究一个四代中国家庭中X连锁遗传性感音神经性听力损失（HL）的致病原因。研究人员通过全外显子组测序（whole-exome sequencing），在SMPX基因中发现了一种全新的重复变异（c.217dupA, p.Ile73Asnfs*5）。该移码突变可导致SMPX蛋白提前截短，且与HL表型共分离，在295名正常对照个体中未检测到此变异。后续，研究人员通过Sanger测序（Sanger sequencing），对338名中国非综合征性HL患者的SMPX基因编码外显子及侧翼内含子进行了亚群筛查，并在另外两例散发性先天性耳聋病例中，发现了SMPX基因的另外两处潜在致病替换（c.238C>A与c.55A>G）。综上，本研究首次报道了SMPX基因在中国人群中的致病作用，并鉴定出一种全新的移码突变，该突变不仅可引发非综合征性迟发型进行性HL，还可导致先天性听力障碍。本研究结果拓展了SMPX基因的突变谱与表型谱。