Blanco-Kelly Fiona, Jaijo Teresa, Aller Elena, Avila-Fernandez Almudena, López-Molina María Isabel, Giménez Ascensión, García-Sandoval Blanca, Millán José M, Ayuso Carmen
Servicio de Genética, Instituto de Investigación-Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain2Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain.
Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain3Grupo de Investigación en Enfermedades Neurosensoriales, Instituto de Investigación Sanitaria-La Fe, Valencia, Spain.
JAMA Ophthalmol. 2015 Feb;133(2):157-64. doi: 10.1001/jamaophthalmol.2014.4498.
A new statistical approach is needed to describe the clinical differences between type I and type II Usher syndrome and between the 2 most frequent mutations in the USH2A gene.
To describe the primary phenotypic characteristics and differences between type I and type II Usher syndrome and to establish a phenotype-genotype correlation for the 2 most frequent mutations in the USH2A gene.
DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study at a genetics department, in which clinical evaluations were performed for 433 patients (297 unrelated families) who were classified as having type I, II, III, atypical, or unclassified Usher syndrome according to their clinical history, pedigree data, results from ophthalmological studies, and audiological, neurophysiological, and vestibular test results. Molecular studies were performed for 304 patients (256 unrelated families). The Mann-Whitney U test or the χ2 test was used for calculating the differences between mean values for the analyzed parameters.
Age at diagnosis; age at onset of night blindness, visual field loss, visual acuity loss, and cataracts; and severity and age at diagnosis of hearing loss.
The comparison between patients with type I Usher syndrome and those with type II Usher syndrome revealed P < .001 for most items analyzed. The most frequent mutations in the USH2A gene were the p.Glu767Serfs21 and p.Cys759Phe mutations, with an allelic frequency of 23.2% (63 of 272 alleles) and 8.1% (22 of 272 alleles), respectively. The phenotypic analysis for patients carrying p.Cys759Phe showed P < .001 for most items analyzed when compared with patients carrying p.Glu767Serfs21 and when compared with patients carrying other mutations in the USH2A gene. None of the p.Cys759Phe patients exhibited a severe hearing loss phenotype, and more than 60% had only mild hearing loss. Most patients carrying the p.Glu767Serfs*21 mutation (72.1%) were moderately deaf.
Our study presents the clinical differences between type I and type II Usher syndrome and between the 2 most frequent mutations in the USH2A gene. Detailed genotype-phenotype correlations, as presented in our study, allow for a better correlation of clinical signs with a known genotype and can improve the clinical management, genetic counseling, and risk assessment of patients with Usher syndrome because an estimated prognosis of their disease can be made.
需要一种新的统计方法来描述I型和II型Usher综合征之间以及USH2A基因中两种最常见突变之间的临床差异。
描述I型和II型Usher综合征的主要表型特征及差异，并建立USH2A基因中两种最常见突变的表型-基因型相关性。
设计、地点和参与者：在一个遗传学部门进行的横断面研究，对433例患者（297个无亲缘关系的家庭）进行了临床评估，这些患者根据其临床病史、家系数据、眼科研究结果以及听力、神经生理学和前庭测试结果被分类为患有I型、II型、III型、非典型或未分类的Usher综合征。对304例患者（256个无亲缘关系的家庭）进行了分子研究。采用Mann-Whitney U检验或χ2检验计算分析参数均值之间的差异。
诊断年龄；夜盲、视野缺损、视力丧失和白内障的发病年龄；以及听力损失的严重程度和诊断年龄。
I型Usher综合征患者与II型Usher综合征患者之间的比较显示，在分析的大多数项目中P＜0.001。USH2A基因中最常见的突变是p.Glu767Serfs21和p.Cys759Phe突变，等位基因频率分别为23.2%（272个等位基因中的63个）和8.1%（272个等位基因中的22个）。与携带p.Glu767Serfs21的患者以及与携带USH2A基因其他突变的患者相比，携带p.Cys759Phe的患者的表型分析显示，在分析的大多数项目中P＜0.001。没有p.Cys759Phe患者表现出严重听力损失表型，超过60%的患者只有轻度听力损失。大多数携带p.Glu767Serfs*21突变的患者（72.1%）为中度耳聋。
我们的研究呈现了I型和II型Usher综合征之间以及USH2A基因中两种最常见突变之间的临床差异。如我们研究中所示的详细的基因型-表型相关性，能够使临床体征与已知基因型有更好的相关性，并且可以改善Usher综合征患者的临床管理、遗传咨询和风险评估，因为可以对他们疾病的预后进行估计。
