背景:Usher综合征(USH)是一种常染色体隐性遗传疾病,主要影响听力,愿景,and,在某些情况下,前庭功能。USH,根据发病年龄,严重程度,和症状的进展,分为四种主要类型。此外,有大量报告表明患者的表现偏离了USH主要类型的典型表型标准,被称为非典型USH。CDH23是第二个最常见的USH基因,其缺陷导致USH1D,非综合征性常染色体隐性遗传性耳聋-12(DFNB12),在一些情况下,非典型USH1D。虽然一些研究表明,CDH23基因中的错义和截短破坏性变异会导致DFNB12和USH1D,分别,尚未确定非典型USH1D的基因型-表型相关性.
方法:使用全外显子组测序,我们研究了一个伊朗家庭,有两个兄弟姐妹,他们表现出先天性双侧听力损失,迟发性夜盲症,视网膜色素变性,前庭功能正常,表明他们的临床症状与USH2一致。
结果:全外显子组数据分析揭示了CDH23基因中的一个新的双等位基因无义变体(c.6562G>T;p.Glu2188Ter),Sanger测序证实了这一点。令人惊讶的是,CDH23是USH1基因的成员;因此,我们的患者患有非典型USH1D.此外,通过文献综述,我们提供了所有报告的具有非典型表现的患者或驳斥了声称的基因型-表型相关性的患者的临床和突变谱.
结论:通过报告一种新的破坏性变体,我们扩大了导致非典型USH1D的CDH23基因的突变谱。此外,回顾文献表明,与以前的说法相反,不同的基因型发生在CDH23基因等位基因疾病,并且没有明确的基因型-表型相关性。
Usher syndrome (USH) is an autosomal recessive disorder that predominantly affects hearing, vision, and, in some cases, vestibular function. USH, according to the onset age, severity, and progression of symptoms, is categorized into four main types. In addition, there are a significant number of reports that patients\' manifestations deviate from canonical phenotypic criteria of main types of USH, which are named atypical USH. CDH23 is the second most common USH gene in which its defects result in USH1D, non-syndromic autosomal recessive deafness-12 (DFNB12), and in a few cases, atypical USH1D. While some studies have suggested that missense and truncating damaging variants in the CDH23 gene cause DFNB12 and USH1D, respectively, no genotype-phenotype correlation for atypical USH1D has been established.
Using whole-exome sequencing, we studied an Iranian family with two affected siblings who manifested congenital bilateral hearing loss, late-onset nyctalopia, retinitis pigmentosa, and normal vestibular function, indicating that their clinical symptoms are consistent with USH2.
Whole-exome data analysis revealed a novel bi-allelic nonsense variant (c.6562G>T; p.Glu2188Ter) in the CDH23 gene, which was confirmed by Sanger sequencing. Surprisingly, CDH23 is a member of the USH1 genes; therefore, our patients suffered from atypical USH1D. Also, by conducting a literature
review, we provided a clinical and mutational profile of all reported patients with atypical manifestations or those who refuted the claimed genotype-phenotype correlation.
By reporting a novel damaging variant, we expand the mutational spectrum of the CDH23 gene that leads to atypical USH1D. Also, reviewing the literature shows that, contrary to previous claims, different genotypes occur in the CDH23 gene allelic disorders, and there is no clear-cut genotype-phenotype correlation.