Rare genetic causes of complex kidney and urological diseases.
Rare genetic causes of complex kidney and urological diseases.
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DOI：
10.1038/s41581-020-0325-2
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发表时间：
2020-11
期刊：
影响因子：
--
通讯作者：
Gharavi AG
中科院分区：
文献类型：
--
作者：
Groopman EE;Povysil G;Goldstein DB;Gharavi AG
虽然通常被认为是单一实体，但慢性肾脏疾病（CKD）包括许多导致持续异常肾脏结构和/或功能的病理生理学上不同的疾病，并且包括单基因和多基因病因。罕见的CKD遗传形式经常跨越不同的表型，反映了遗传现象，包括多效性，不完全显性和可变表达。染色体微阵列和大规模平行测序技术的使用揭示了基因组疾病和单基因病因在不同临床定义的亚组中对看似复杂的CKD形式有意义的贡献，并且以高遗传和表型异质性为特征。对CKD中流行的基因组疾病的研究已经整合了遗传学、生物信息学和功能研究，以确定其肾和肾外表现的遗传驱动因素，揭示了单基因和多基因机制。类似地，基于大规模平行测序的分析已经确定了基因和等位基因水平的变异，这些变异有助于在许多单基因型肾病中观察到临床上多样化的表型。全基因组测序研究表明，在至少5%的患者中发现了双重遗传诊断，其中确定了疾病的遗传原因，突出了复杂的表型也可能来自多位点变异的事实。一种多方面的方法，结合了来自大型，多样化队列的遗传和表型数据，将有助于阐明不同形式CKD的基因型和表型之间的复杂关系，支持肾病个体的个性化治疗。
Although often considered a single-entity, chronic kidney disease (CKD) comprises many pathophysiologically distinct disorders that result in persistently abnormal kidney structure and/or function, and encompass both monogenic and polygenic aetiologies. Rare inherited forms of CKD frequently span diverse phenotypes, reflecting genetic phenomena including pleiotropy, incomplete penetrance and variable expressivity. Use of chromosomal microarray and massively parallel sequencing technologies has revealed that genomic disorders and monogenic aetiologies contribute meaningfully to seemingly complex forms of CKD across different clinically defined subgroups and are characterized by high genetic and phenotypic heterogeneity. Investigations of prevalent genomic disorders in CKD have integrated genetic, bioinformatic and functional studies to pinpoint the genetic drivers underlying their renal and extra-renal manifestations, revealing both monogenic and polygenic mechanisms. Similarly, massively parallel sequencing-based analyses have identified gene- and allele-level variation that contribute to the clinically diverse phenotypes observed for many monogenic forms of nephropathy. Genome-wide sequencing studies suggest that dual genetic diagnoses are found in at least 5% of patients in whom a genetic cause of disease is identified, highlighting the fact that complex phenotypes can also arise from multilocus variation. A multifaceted approach that incorporates genetic and phenotypic data from large, diverse cohorts will help to elucidate the complex relationships between genotype and phenotype for different forms of CKD, supporting personalized medicine for individuals with kidney disease.
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DOI：
10.1126/science.aal4043
发表时间：
2018-03-16
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bastarache L;Hughey JJ;Hebbring S;Marlo J;Zhao W;Ho WT;Van Driest SL;McGregor TL;Mosley JD;Wells QS;Temple M;Ramirez AH;Carroll R;Osterman T;Edwards T;Ruderfer D;Velez Edwards DR;Hamid R;Cogan J;Glazer A;Wei WQ;Feng Q;Brilliant M;Zhao ZJ;Cox NJ;Roden DM;Denny JC
通讯作者：
Denny JC
影响因子：
3.9
作者：
Bower, Matthew;Salomon, Remi;Heidet, Laurence
通讯作者：
Heidet, Laurence
影响因子：
2.7
作者：
Chapman, DL;Agulnik, I;Papaioannou, VE
通讯作者：
Papaioannou, VE
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
4.6
作者：
Adam J;Browning AC;Vaideanu D;Heidet L;Goodship JA;Sayer JA
通讯作者：
Sayer JA