Department of Ophthalmology, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland.
JAMA Ophthalmol. 2021 Jul 1;139(7):691-700. doi: 10.1001/jamaophthalmol.2021.0385.
Identification of geographic population-based differences in genotype and phenotype heterogeneity are important for targeted and patient-specific diagnosis and treatment, counseling, and screening strategies.
To report disease-causing variants and their detailed phenotype in patients with bilateral congenital cataract from a single center in Switzerland and thereby draw a genetic map and perform a genotype-phenotype comparison of this cohort.
DESIGN, SETTING, AND PARTICIPANTS: This clinical and molecular-genetic cohort study took place through the collaboration of the Department of Ophthalmology at the University Hospital Zurich and the Institute of Medical Molecular Genetics, University of Zurich, Schlieren, Switzerland. Thirty-seven patients from 25 families with different types of bilateral congenital cataract were included. All participating family members received a comprehensive eye examination. Whole exome sequencing was performed in the index patients, followed by a filtering process to detect possible disease-associated variants in genes previously described in association with congenital cataract. Probable disease-causing variants were confirmed by Sanger sequencing in available family members. All data were collected from January 2018 to June 2020, and the molecular-genetic analyses were performed from January 2019 to July 2020.
Identification of the underlying genetic causes of bilateral congenital cataract, including novel disease-causing variants and phenotype correlation.
Among the 37 patients (18 [49%] male and 19 [51%] female; mean [SD] age, 17.3 [15.9] years) from 25 families, pathogenic variants were detected in 20 families (80% detection rate), which included 13 novel variants in the following genes: BCOR, COL4A1, CRYBA2, CRYBB2, CRYGC, CRYGS, GJA3, MAF, NHS, and WFS1. Putative disease-causing variants were identified in 14 of 20 families (70%) as isolated cases and in 6 of 20 families (30%) with syndromic cases. A recessive variant in the CRYBB2 gene in a consanguineous family with 2 affected siblings showing a nuclear and sutural cataract was reported in contrast to previously published reports. In addition, the effect on splicing in a minigene assay of a novel splice site variant in the NHS gene (c.[719-2A>G]) supported the pathogenicity of this variant.
This study emphasizes the importance of genetic testing of congenital cataracts. Known dominant genes need to be considered for recessive inheritance patterns. Syndromic types of cataract may be underdiagnosed in patients with mild systemic features.
确定基因型和表型异质性的地理人群差异对于有针对性的个体化诊断和治疗、咨询以及筛查策略非常重要。
报告来自瑞士单一中心的双侧先天性白内障患者的致病变异及其详细表型，从而绘制该队列的遗传图谱并进行基因型-表型比较。
设计、地点和参与者：这项临床和分子遗传学队列研究是由苏黎世大学医院眼科和苏黎世大学医学分子遗传学研究所合作进行的，地点在瑞士施利伦。纳入了 25 个不同类型双侧先天性白内障家系的 37 名患者。所有参与的家族成员都接受了全面的眼部检查。对索引患者进行全外显子组测序，然后进行过滤过程，以检测先前与先天性白内障相关的基因中可能与疾病相关的变异。在可用的家族成员中通过 Sanger 测序确认可能的致病变异。所有数据均于 2018 年 1 月至 2020 年 6 月收集，分子遗传学分析于 2019 年 1 月至 2020 年 7 月进行。
确定双侧先天性白内障的潜在遗传原因，包括新的致病变异和表型相关性。
在 25 个家系的 37 名患者（18 名[49%]为男性，19 名[51%]为女性；平均[标准差]年龄为 17.3[15.9]岁）中，在 20 个家系（80%的检出率）中检测到致病性变异，包括以下基因中的 13 个新变异：BCOR、COL4A1、CRYBA2、CRYBB2、CRYGC、CRYGS、GJA3、MAF、NHS 和 WFS1。在 20 个家系中的 14 个（70%）作为孤立病例和 6 个（30%）作为综合征病例中发现了推定的致病变异。在一个有 2 名受影响同胞的近亲家系中，报道了 CRYBB2 基因中的隐性变异，表现为核性和缝合性白内障，这与以前的报道相反。此外，在 NHS 基因中的新型剪接位点变异（c.[719-2A>G]）的小基因检测中，剪接的影响支持该变异的致病性。
本研究强调了对先天性白内障进行基因检测的重要性。需要考虑显性基因的隐性遗传模式。具有轻度全身特征的综合征型白内障可能诊断不足。
