# Improving the Diagnosis of Congenital Genitourinary Birth Defects

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2021 · $381,375

## Abstract

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.

## Key facts

- **NIH application ID:** 10063826
- **Project number:** 5R01DK078121-13
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Dolores Jean Lamb
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,375
- **Award type:** 5
- **Project period:** 2007-12-01 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10063826

## Citation

> US National Institutes of Health, RePORTER application 10063826, Improving the Diagnosis of Congenital Genitourinary Birth Defects (5R01DK078121-13). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10063826. Licensed CC0.

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