The overall goal of this project is to identify the cause of Prune Belly Syndrome (PBS), a multi-system congenital human urologic anomaly. We are taking 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 ureters, and 3) bilateral undescended testes.
Its morbidity and mortality are devastating: 20 percent of babies are stillborn, 43 percent are born prematurely, and 30 percent die of renal failure or urosepsis by age 2. PBS most frequently affects boys.
Our NIH-funded study has worked extensively with the Prune Belly Syndrome Network (PBSN), the largest US family support group for PBS. With the help of this organization, more than 300 people from more than 100 families have provided us with medical information and DNA samples. Several families have had more than one child with PBS; these families are called multiplex PBS kindreds, and they are especially helpful in accelerating the pace of discovery.
In some kindreds, the inheritance pattern supports 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.
We are using Next Generation Sequencing to identify genes that cause PBS, and we are studying the functional impact of clinical mutations in these genes. Using whole-exome DNA sequencing, we have identified candidate PBS genes with mutations. One especially interesting mutation found in two brothers with PBS affects muscle cells. We are further testing the mutation to unravel how it causes PBS.
More individuals and multiplex families with PBS are needed for this study.