Center for Human Disease Modeling, Duke University, Durham, North Carolina, USA; Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, USA (current address).
Department of Medicine, Division of Nephrology, Columbia University Irving Medical Center, New York, New York, USA.
Kidney Int. 2022 Mar;101(3):473-484. doi: 10.1016/j.kint.2021.09.034. Epub 2021 Nov 12.
Advances in clinical diagnostics and molecular tools have improved our understanding of the genetically heterogeneous causes underlying congenital anomalies of kidney and urinary tract (CAKUT). However, despite a sharp incline of CAKUT reports in the literature within the past 2 decades, there remains a plateau in the genetic diagnostic yield that is disproportionate to the accelerated ability to generate robust genome-wide data. Explanations for this observation include (i) diverse inheritance patterns with incomplete penetrance and variable expressivity, (ii) rarity of single-gene drivers such that large sample sizes are required to meet the burden of proof, and (iii) multigene interactions that might produce either intra- (e.g., copy number variants) or inter- (e.g., effects in trans) locus effects. These challenges present an opportunity for the community to implement innovative genetic and molecular avenues to explain the missing heritability and to better elucidate the mechanisms that underscore CAKUT. Here, we review recent multidisciplinary approaches at the intersection of genetics, genomics, in vivo modeling, and in vitro systems toward refining a blueprint for overcoming the diagnostic hurdles that are pervasive in urinary tract malformation cohorts. These approaches will not only benefit clinical management by reducing age at molecular diagnosis and prompting early evaluation for comorbid features but will also serve as a springboard for therapeutic development.
临床诊断和分子工具的进步提高了我们对导致肾和尿路先天异常（CAKUT）的遗传异质性原因的理解。然而，尽管在过去 20 年中，文献中 CAKUT 的报告急剧增加，但遗传诊断的收益仍处于高原状态，与加速生成强大全基因组数据的能力不成比例。造成这种观察结果的原因包括：（i）不完全外显率和可变表达率的多种遗传模式，（ii）单基因驱动的罕见性，因此需要大样本量才能满足证据负担，以及（iii）多基因相互作用，可能导致（例如，拷贝数变异）或（例如，跨位效应）的基因内或基因间效应。这些挑战为社区提供了一个机会，可以采用创新的遗传和分子途径来解释遗传缺失，并更好地阐明导致 CAKUT 的机制。在这里，我们回顾了遗传学、基因组学、体内建模和体外系统之间的最新多学科方法，以完善克服普遍存在于尿路畸形队列中的诊断障碍的蓝图。这些方法不仅将通过减少分子诊断的年龄和促使对合并症特征进行早期评估来有益于临床管理，而且还将成为治疗开发的跳板。
