Angie C. Jelin ^1* Nikolai Sopko ¹ Nara Sobreira ¹ Simeon A. Boyadjiev ² Elizabeth Wohler ¹ Christian Morrill ¹ Dane Witmer ¹ Jason Michaud ¹ David Valle ³ John Gearhart ¹ Heather Dicarlo ¹

• ¹ The Johns Hopkins Hospital, Johns Hopkins Medicine, Baltimore, Maryland, United States
• ² University of California, Davis, Davis, California, United States
• ³ Johns Hopkins Medicine, Johns Hopkins University, Baltimore, Maryland, United States

Introduction/background: Bladder exstrophy epispadias complex (BEEC) is a rare congenital anomaly of unknown etiology, although, genetic and environmental factors have been associated with its development. Variants in several genes expressed in the urogenital pathway have been reported as causative for bladder exstrophy in human and murine models. The expansion of next generation sequencing and molecular genomics has improved our ability to identify the underlying genetic causes of similarly complex diseases and could thus assist with the investigation of the molecular basis of BEEC.Objective: The objective was to identify the presence of rare heterozygous variants in genes previously implicated in bladder exstrophy and correlate them with the presence or absence of bladder regeneration in our study population.Patients and Methods: We present a case series of patients with BEEC whom had bladder biopsies performed by pediatric urology during bladder neck reconstruction or bladder augmentation. Cases were classified as "sufficient" or "insufficient" based on a bladder volume of greater than or less than 40% of expected bladder size. Control bladder tissue specimens were obtained from patients undergoing biopsies for conditions other than bladder exstrophy. Whole exome sequencing was performed on the specimens and the identified variants were compared. Based on the hypothesis of de novo mutations, as well as the potential implications of autosomal dominant conditions with incomplete penetrance, each case was evaluated for autosomal dominant variants in a set of genes previously implicated in BEEC.Results: Whole exome sequencing was performed on DNA extracted from bladder tissue from 5 cases classified as sufficient, 7 cases classified as insufficient, and 6 controls. Our review of the literature identified 44 genes that have been implicated in human models of bladder exstrophy. Our whole exome sequencing data analysis identified rare variants in 2 genes among the cases classified as sufficient, and 7 variants in 5 genes among the cases classified as insufficient.We identified rare variants in previously implicated genes in the majority of our BEEC specimens. Our findings could have implications for prognostic counseling. Additional research is needed to further understand the cellular signaling underlying this potentially genetically heterogeneous embryological condition.