Improving the Diagnosis of Congenital Genitourinary Birth Defects

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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.