背景:Usher综合征(USH)是一种常染色体隐性遗传疾病,主要导致聋盲。Usher综合征1型(USH1)亚型患者通常经历先天性感觉神经性听力损失,前庭功能异常,和视网膜色素变性(RP)。在这里,我们介绍了一例Usher综合征1F型(USH1F),在钙依赖性细胞粘附原钙粘蛋白15(PCDH15)基因中具有新的纯合变体。
方法:对眼科检查进行了为期10年的评估,并通过全外显子组测序(WES)鉴定了致病变异。10年后对彩色眼底照片的初始和随访检查显示,双眼中的骨针色素沉积增加。在眼底自发荧光(FAF)中显示出双眼的旁凹高AF环,并在8年内观察到渐进的直径方向收缩。在光谱域光学相干断层扫描(SD-OCT)上,在双眼的副凹和中央凹区域观察到外核层(ONL)丢失。全视野视网膜电图(ffERG)显示整体视网膜功能消失。WES鉴定了一个新的两碱基对缺失,c.60_61del(p.Phe21Ter),在PCDH15基因中,确认诊断为USS1F。
结论:我们报道了一种新的纯合PCDH15致病变体,预计会导致PCDH15mRNA的无义介导的衰变(NMD)。患者表现出USH1F功能丧失,经历先天性听力损失和综合征性RP。
BACKGROUND: Usher syndrome (USH) is an autosomal recessive disorder primarily responsible for deaf-blindness. Patients with subtype Usher syndrome type 1 (USH1) typically experience congenital sensorineural hearing loss, abnormal vestibular function, and retinitis pigmentosa (RP). Here we present a case of Usher syndrome type 1F (USH1F) with a novel homozygous variant in the calcium-dependent cell-cell adhesion protocadherin-15 (PCDH15) gene.
METHODS: Ophthalmic examinations were evaluated over a course of 10 years and the disease-causing variant was identified by whole exome sequencing (WES). Initial and follow-up examination of color fundus photos after 10 years revealed an increase in bone spicule pigment deposits in both eyes. A parafoveal hyper-AF ring in both eyes was shown in fundus autofluorescence (FAF) with a progressive diameter-wise constriction observed over 8 years. Outer nuclear layer (ONL) loss was observed in parafoveal and perifoveal regions of both eyes on spectral domain-optical coherence tomography (SD-OCT). Full-field electroretinography (ffERG) showed extinguished global retinal function. WES identified a novel two-base-pair deletion, c.60_61del (p.Phe21Ter), in the PCDH15 gene, confirming the diagnosis of USH1F.
CONCLUSIONS: We report a novel homozygous PCDH15 pathogenic variant expected to lead to nonsense-mediated decay (NMD) of PCDH15 mRNA. The patient exhibits a loss of function with USH1F, experiencing congenital hearing loss and syndromic RP.