Prune Belly Syndrome

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 DESCRIPTION (provided by applicant): The overall goal of this project is to expand the knowledge on the genetic basis and molecular mechanisms of Prune Belly Syndrome (PBS), a severe multi-system congenital human urologic anomaly. We will take a personalized medicine approach to identifying the molecular cause of this rare but severe disorder. The hallmark features of PBS include the triad of: 1) hypoplastic or absent abdominal wall skeletal musculature, 2) bladder smooth muscle dysplasia leading to urinary tract dilation with megacystis and refluxing, and 3) bilateral undescended testes. Despite its rarity and prenatal detection, PBS is often devastating, with 20% stillborn, 43% born premature, and 30% dying of renal failure or urosepsis by age 2 years. Male predominance and familial cases of PBS support a sex-limited autosomal recessive or X-linked inheritance. Recently, several genes have been implicated in PBS, but the overwhelming majority of PBS patients do not carry genomic variants in these genes. Thus, additional PBS-causing genes remain unknown. Our study will take advantage of a large cohort of PBS probands and the multiplex PBS kindreds we have recruited. We will use next generation sequencing to identify novel genes causing PBS, and we will study the functional impact of clinical mutations in these genes. Our specific aims are to: 1) identify novel causal genomic variants for PBS, 2) characterize the molecular signature of PBS affected organs, and 3) characterize the role of our recently identified PBS candidate gene.