Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center
Molecular genetic findings and clinical correlations in 100 patients with Joubert syndrome and related disorders prospectively evaluated at a single center
复制标题
DOI：
10.1038/gim.2016.204
复制
发表时间：
2017-08-01
影响因子：
8.8
通讯作者：
Gunay-Aygun, Meral
中科院分区：
文献类型：
--
作者：
Vilboux, Thierry;Doherty, Daniel A.;Gunay-Aygun, Meral
目的：Joubert综合征（JS）是一种遗传和临床异质性纤毛病变，其特征是独特的小脑和脑干畸形，导致诊断性的“臼齿征”的脑成像。迄今为止，已确定了30多个JS基因，但这些并不占所有patients.Methods：在我们的队列中的100例JS患者从86个家庭，我们前瞻性地进行了广泛的临床评估，并提供分子诊断使用靶向27基因的分子倒置探针面板，然后全外显子组测序（WES）。在20个基因中发现了126个（27个新的）独特的潜在致病性变异，包括KIAA 0753和CELSR 2，这些基因以前与JS无关。基因型-表型相关性揭示了TMEM 67、C5 orf 52或KIAA 0586变异患者没有视网膜变性。脉络膜视网膜缺损与视网膜变性风险降低和肝脏疾病风险增加相关。TMEM 67是经常与肾脏diseases.Conclusion：在JS中，WES显着提高产量的分子诊断，这是必不可少的生殖咨询和选择植入前和产前诊断以及医疗管理和预后咨询的年龄依赖性和进行性器官特异性表现，包括视网膜，肝脏和肾脏疾病。
Purpose: Joubert syndrome (JS) is a genetically and clinically heterogeneous ciliopathy characterized by distinct cerebellar and brain-stem malformations resulting in the diagnostic "molar tooth sign" on brain imaging. To date, more than 30 JS genes have been identified, but these do not account for all patients.Methods: In our cohort of 100 patients with JS from 86 families, we prospectively performed extensive clinical evaluation and provided molecular diagnosis using a targeted 27-gene Molecular Inversion Probes panel followed by whole-exome sequencing (WES).Results: We identified the causative gene in 94% of the families; 126 (27 novel) unique potentially pathogenic variants were found in 20 genes, including KIAA0753 and CELSR2, which had not previously been associated with JS. Genotype-phenotype correlation revealed the absence of retinal degeneration in patients with TMEM67, C5orf52, or KIAA0586 variants. Chorioretinal coloboma was associated with a decreased risk for retinal degeneration and increased risk for liver disease. TMEM67 was frequently associated with kidney disease.Conclusion: In JS, WES significantly increases the yield for molecular diagnosis, which is essential for reproductive counseling and the option of preimplantation and prenatal diagnosis as well as medical management and prognostic counseling for the age-dependent and progressive organ-specific manifestations, including retinal, liver, and kidney disease.