Genomic Approaches to Congenital Genitourinary Disorders

Congenital genitourinary disorders are the third most common congenital anomaly worldwide (1 in 135 births) and include anomalies of both the urinary and genital systems, such as prune belly syndrome (PBS), persistent cloaca, and disorders of sex development (DSD). Understanding the genetic cause of a disease plays a major role in clinical diagnosis, management, and treatment; however the underlying causative genes for PBS and persistent cloaca are unknown while mutations in known DSD genes account for only 50% of 46,XY DSD patients. The goal of this research was to use both array-comparative genomic hybridization and whole exome sequencing to identify causative variants and candidate genes for PBS, persistent cloaca, and DSD. Sequencing the exomes of two PBS brothers identified a missense mutation in Filamin A and functional testing suggests this mutation impairs muscle cell contraction and mechanosensing. Candidate genes identified from sequencing the exomes of unrelated patients are hypothesized to have similar effects on cellular function, suggesting a common causative pathway may contribute to PBS pathogenesis. Additionally, structural variants identified by array-comparative genomic hybridization propose both candidate regions for persistent cloaca and novel variants in DSD pathogenesis. Both genome-wide tests identified novel or rare candidate genes for further study indicating that continued genetic testing of patients with congenital genitourinary disorders will lead to a better understanding of molecular pathways of disease pathogenesis and clinical care.