A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases
A kidney-disease gene panel allows a comprehensive genetic diagnosis of cystic and glomerular inherited kidney diseases
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DOI：
10.1016/j.kint.2018.02.027
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发表时间：
2018-08-01
影响因子：
19.6
通讯作者：
Ars, Elisabet
中科院分区：
文献类型：
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作者：
Bullich, Gemma;Domingo-Gallego, Andrea;Ars, Elisabet
遗传性肾脏疾病的分子诊断仍然是一个挑战，由于其不断扩大的表型谱以及不断增长的致病基因列表。在这里，我们发展了一个全面的方法遗传诊断遗传性囊性和肾小球肾病。对421例患者、116例已知突变患者的验证队列、207例疑似遗传性囊性肾病患者和98例肾小球疾病患者的诊断队列进行了140个导致囊性或肾小球肾病或与之相关的基因的下一代靶向测序。在验证队列中，灵敏度达到99%。在诊断队列中，在78%的囊性疾病患者和62%的肾小球疾病患者中发现了致病突变，其中大多数是家族性病例，包括拷贝数变异。结果描述了不同囊性和肾小球遗传性疾病的分布，显示了根据围产期、儿童和成人发病最可能的诊断。在所有基因诊断的患者中，15%的患者转诊时有未明确的临床诊断，2%的患者基因检测改变了临床诊断。因此，在17%的病例中，我们的基因分析是建立正确诊断的关键。常染色体显性多囊肾病和Alport综合征的复杂遗传模式分别在7例和6例患者中被怀疑。因此，我们的肾脏疾病基因面板是一种全面、无创、经济有效的遗传诊断囊性和肾小球遗传性肾脏疾病的工具。这使得四分之三的患者可以进行病因诊断，对于非特异性或非典型表型的患者尤其有价值。
Molecular diagnosis of inherited kidney diseases remains a challenge due to their expanding phenotypic spectra as well as the constantly growing list of disease-causing genes. Here we develop a comprehensive approach for genetic diagnosis of inherited cystic and glomerular nephropathies. Targeted next generation sequencing of 140 genes causative of or associated with cystic or glomerular nephropathies was performed in 421 patients, a validation cohort of 116 patients with previously known mutations, and a diagnostic cohort of 207 patients with suspected inherited cystic disease and 98 patients with glomerular disease. In the validation cohort, a sensitivity of 99% was achieved. In the diagnostic cohort, causative mutations were found in 78% of patients with cystic disease and 62% of patients with glomerular disease, mostly familial cases, including copy number variants. Results depict the distribution of different cystic and glomerular inherited diseases showing the most likely diagnosis according to perinatal, pediatric and adult disease onset. Of all the genetically diagnosed patients, 15% were referred with an unspecified clinical diagnosis and in 2% genetic testing changed the clinical diagnosis. Therefore, in 17% of cases our genetic analysis was crucial to establish the correct diagnosis. Complex inheritance patterns in autosomal dominant polycystic kidney disease and Alport syndrome were suspected in seven and six patients, respectively. Thus, our kidney-disease gene panel is a comprehensive, noninvasive, and cost-effective tool for genetic diagnosis of cystic and glomerular inherited kidney diseases. This allows etiologic diagnosis in three-quarters of patients and is especially valuable in patients with unspecific or atypical phenotypes.