Improving the Diagnosis of Congenital Genitourinary Birth Defects

总的来说，先天性泌尿生殖系统（GU）出生缺陷是最常见的出生缺陷， 男性，但对他们的原因知之甚少。这在一定程度上反映了当前临床 这种观点认为，由于大多数出生缺陷都可以通过手术修复， 通过了解原因来获得。因此，相对较少的研究 直到最近才被执行。然而，我们的研究表明，看似简单的出生缺陷， 尿道下裂或隐睾，可能与其他更重要的低估 缺陷，如影响肾脏、心脏、眼睛或行为的缺陷。染色体研究 GU个体中的微缺失和微重复（称为拷贝数变异，CNVs） 使我们能够检验CNV编码基因的基因剂量变化的假设 区域是泌尿生殖系统发育的重要调节器，当单倍不足或 重复的正常泌尿生殖系统发育受到影响，导致上部的出生缺陷 和/或下泌尿生殖道。我们成功地利用这一策略识别了15种不同的 以前未被识别的基因，当微复制或微缺失时， 例如隐睾症、尿道下裂、性别模糊（性分化障碍- 先天性肾脏和泌尿道畸形（CAKUT），以及严重的出生缺陷。 缺陷，如膀胱外翻尿道上裂综合征（BEEC）。因果关系得到证实 通过识别所涉及的机制，并通过重新投降的出生缺陷， 单倍不足或过度表达的动物模型。值得注意的是， 这些变化影响了新的， 以前不知道的方法。在本建议中，我们重点定义了两种机制， 在阴茎异常患者中常发生微缺失的候选基因。我们将测试 假设22q13.3处RBFOX 2 CNVs通过产生替代基因而导致GU异常 FGFR 2剪接变体（FGFR 2 IIIc代替FGFR 2 IIIb）阻碍阴茎生长和尿道 发展第二个假设是9p24.3的Kank 1缺失使β-连环蛋白钝化 生殖器结节发育过程中FGF 8表达的调节导致阴茎异常。 这些研究不仅将确定以前未被认识到的GU异常的原因， 这些基因剂量变化的额外的相关后遗症。在未来，这样的知识 可能导致改善诊断和治疗方法，以改善这些常见的出生 缺陷

Collectively, congenital genitourinary (GU) birth defects are the most common birth defects in males, yet relatively little is known about their cause. In part, this reflects the current clinical perspective that, because most of these birth defects can be surgically repaired, there is nothing to be gained by understanding the cause. Accordingly, relatively little research has been performed until recently. Yet our studies suggest that seemingly simple birth defects like hypospadias or cryptorchidism, may be associated with other more significant underappreciated defects, such as those affecting the kidney, heart, eyes or behavior. Studies of chromosome microdeletions and microduplications (called copy number variations, CNVs) in GU individuals enabled us to test the hypothesis that gene-dosage changes in gene(s) encoded in CNV regions are important regulators of genitourinary development and when haploinsufficient or duplicated normal genitourinary development is impacted causing birth defects of the upper and/or lower genitourinary tract. We successfully used this strategy to identify 15 different previously unrecognized genes that when microduplicated or microdeleted result in conditions such as cryptorchidism, hypospadias, sexual ambiguity (disorders of sexual differentiation- DSD), congenital anomalies of the kidney and urinary track (CAKUT), as well as severe birth defects such as bladder exstrophy epispadias complex (BEEC). Causation was demonstrated through identification of the mechanisms involved and through re-capitulation of the birth defect with animal models of haploinsufficiency or over-expression. Remarkably, gene-dosage changes affected major signaling pathways and post-translational modifications in novel, previously unrecognized ways. In this proposal, we focus on defining the mechanisms of two candidate genes commonly microdeleted in patients with penile anomalies. We will test the hypothesis that RBFOX2 CNVs at 22q13.3 contribute to GU anomalies by producing alternate splice variants of FGFR2 (FGFR2IIIc instead of FGFR2IIIb) hindering penile growth and urethral development. The second hypothesis is that Kank1 deletion at 9p24.3 blunts β-catenin regulation of FGF8 expression during genital tubercle development causing penile anomalies. These studies will not only identify previously unrecognized causes of GU anomalies but also additional, associated sequelae of these gene dosage changes. In the future, such knowledge may lead to improved diagnosis and therapeutic approaches to ameliorate these common birth defects.