Molecular and epidemiological studies of bladder exstrophy and epispadias complex

Bladder exstrophy and epispadias complex is a rare congenital genitourinary malformation involving a midline closure defect, leaving an open bladder on the lower abdominal wall.

In Sweden, the prevalence is 3:100 000 live births and the male to female ratio is almost equal. It is regarded to result from a disruption during the normal embryogenesis of the urinary bladder. The recurrence risk of bladder exstrophy is around 1 in 70 siblings. Several reports on chromosome aberrations and twin studies support a genetic background, with the 22q11.2 microduplication being the only recurrent genetic finding so far.

The studies in this thesis aimed to answer some questions that the parents of children born with malformations usually have. In particular, why did it occur, what is the recurrence risk, and what is the prognosis.

The first study evaluated the candidate gene ISL1 in 125 Swedish individuals with this malformation using Sanger sequencing. The only novel, potentially pathogenic finding, a missense variant, was inherited from the healthy mother. Thus, we concluded that the role of the ISL1 gene in the pathogenesis of bladder exstrophy is uncommon in our Swedish cohort.

In study II, chromosomal microarray analysis was utilized to detect submicroscopic copy number variants in 140 affected Swedish individuals. The most interesting novel finding was a maternally inherited microdeletion in chromosome Xq23 in a male individual, indicating an X-linked recessive inheritance pattern. We highlighted two matrices of candidate gene networks, including genes in the 22q11 region and genes in the Wnt-signaling pathways.

The third study applied trio-based whole genome sequencing on DNA from 19 affected individuals and their healthy parents, to identify possible causative variants. The results were filtered using a gene panel with 205 candidate genes. A total of 56 variants in 35 genes were identified, including six de novo variants carried by five different affected individuals. We highlight the sticky protein family as a new candidate gene family due to multiple findings in this study and the involvement of these genes in cell adhesion mechanisms.

Study IV focused on the risk for developing urinary bladder cancer in individuals with bladder exstrophy and epispadias complex and consisted of two parts. First, a register study reporting 12 Swedish individuals where almost all of the tumors were of urothelial type and the majority were invasive at the time of diagnosis. Furthermore, a systematic review of the literature summarizing 165 cases, where most of the tumors were non-urothelial, with a majority being adenocarcinomas. Both sub-studies were consistent regarding the young age at cancer diagnosis and mainly in age groups younger than 65 years old. Based on these findings of a higher risk for bladder cancer than previously estimated, we recommend regular screening of the urinary bladder for individuals with bladder exstrophy and epispadias complex, consisting of cystoscopy and urine cytology analysis and starting before the age of 30 years.

List of scientific papers

I. Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort. Samara Arkani, Jia Cao, Johanna Lundin, Daniel Nilsson, Thomas Källman, Gillian Barker, Gundela Holmdahl, Christina Clementsson Kockum, Hans Matsson, Agneta Nordenskjöld. Human Genome Variation. (2018) 5, 18009.
https://doi.org/10.1038/hgv.2018.9

II. Copy number variants suggest different molecular pathways for the pathogenesis of bladder exstrophy. Agneta Nordenskjöld, Samara Arkani, Maria Pettersson, Johanna Winberg, Jia Cao, Magdalena Fossum, Magnus Anderberg, Gillian Barker, Gundela Holmdahl, Johanna Lundin. American Journal of Medical Genetics. Part A, 2023, Vol.191 (2), p.378-390.
https://doi.org/10.1002/ajmg.a.63031

III. Bladder Exstrophy and Epispadias Complex, association with genetic variants based on whole genome sequencing data in 19 family trios. Samara Arkani, Jesper Eisfeldt, Jia Cao, Magnus Anderberg, Gillian Barker, Hans Matsson, Gundela Holmdahl, Anna Lindstrand, Kristina Lagerstedt-Robinson, Agneta Nordenskjöld. [Manuscript]

IV. Urinary Bladder Cancer in Bladder Exstrophy and Epispadias Complex: A Swedish Register Study and a Systematic Review of the Literature. Samara Arkani, Anna Skarin Nordenvall, Lotta Renström Koskela, Gisela Reinfeldt Engberg, Ann Nordgren, Agneta Nordenskjöld. JU Open Plus. 1(3):e00012, March 2023.
https://doi.org/10.1097/JU9.0000000000000014