| 1. |
- Arkani, Samara, et al.
(författare)
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Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort
- 2018
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Ingår i: Human genome variation. - : Springer Nature. - 2054-345X. ; 5:1
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Tidskriftsartikel (refereegranskat)abstract
- Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. Although the malformation is usually sporadic, a genetic background is supported by an increased recurrence risk in relatives, higher concordance rates in monozygotic twins and several associated chromosomal aberrations. Recently, the ISL1 gene was presented as a candidate gene for bladder exstrophy and epispadias complex (BEEC) development in two different studies. In our study, we screened for genetic variants in the ISL1 gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis. In addition, we evaluated ISL1 expression in RNA of human bladder during embryonic and fetal weeks 5–10 relative to that in lung tissue (week 9). In total, 21 single-nucleotide variants were identified, including a potentially novel missense variant, c.137C>G p.(Ala46Gly), substituting a conserved amino acid. This variant was inherited from an unaffected mother. No structural variants were identified. RNA sequencing revealed ISL1 mRNA expression during the critical time frame of human bladder development. In conclusion, we did not detect any known or likely pathogenic variants in the ISL1 gene in 125 Swedish BEEC patients, indicating that variation in the ISL1 gene is not a common genetic mechanism of BEEC development in the Swedish population.
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| 2. |
- Arkani, Samara
(författare)
-
Molecular and epidemiological studies of bladder exstrophy and epispadias complex
- 2023
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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