Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene

Abstract

Background The bladder exstrophy‐epispadias complex (BEEC) is a congenital malformation of the bladder and urethra. The underlying causes of this malformation are still largely unknown; however, aside from environment, genetics is thought to play an essential role. The recurrent 22q11.2 microduplication is the most persistently detected genetic aberration found in BEEC cases. Methods We performed array comparative genomic hybridization (array‐CGH) analysis of 76 Swedish BEEC patients. Statistical analysis was performed on current dataset pooled with previously published data on the 22q11.2 microduplication in BEEC patients. We performed massive parallel sequencing (MPS) of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication followed by functional studies. Results We identified three additional cases with the 22q11.2 microduplication. Pooling data from this study with previously published reports showed a statistically significant enrichment of the 22q11.2 microduplication in BEEC patients (2.61% in cases vs. 0.08% in controls; OR = 32.6; p = 8.7 × 10−4). MPS of the 22q11.2 region in 20 BEEC patients without the 22q11.2 microduplication identified a novel variant in LZTR1 (p.Ser698Phe) in one patient. Functional evaluation of the LZTR1 p.Ser698Phe variant in live NIH 3T3 cells showed that the concentration and cytoplasmic mobility differ between the Lztr1wt and Lztr1mut, indicating a potential functional effect of the LZTR1mut. Conclusion Our study further emphasizes the involvement of the 22q11.2 region in BEEC development and highlights LZTR1 as a candidate gene underlying the urogenital malformation.

Copy number variants suggest different molecular pathways for the pathogenesis of bladder exstrophy

“…We have previously identified altogether five typical 22q11‐duplications associated with BEEC (Lundin et al, 2010 , 2019 ). The prevalence in our material is 3.4% in reported BEEC patients as compared with 0.08% in controls (Lundin et al, 2010 ).…”

“…All BEEC patients, adults and children, were recruited from the Pediatric Surgery Departments in Stockholm, Göteborg, Uppsala, and Lund, Sweden. Six patients with previously published chromosome aberrations were excluded from the study (Lundin et al, 2010 , 2019 ; Soderhall et al, 2014 ). Blood or excess bladder or skin tissue obtained during surgery was collected for DNA isolation and molecular genetic analysis.…”

“…The candidate region was diminished after new findings of smaller regions of overlap and together with expression pattern the main candidate genes are the CRKL , THAP7 , and LZTR1 genes (Draaken et al, 2014 ). In addition, our group detected one novel mutation in the LZTR1 gene located in this region in a patient with CBE and could show that the mutation has functional effect in the Golgi apparatus (Lundin et al, 2019 ).…”

“…The only recurrent genetic finding so far is the 22q11‐duplication encompassing ~3 Mbp and including 50 genes (Draaken et al, 2010 , 2014 ; Lundin et al, 2010 , 2019 ; Pierquin & Uwineza, 2012 ). The 22q11 duplication syndrome was initially described in 2008 and was mainly associated with cognitive deficits and dysmorphic facial features.…”

The Genomic Architecture of Bladder Exstrophy Epispadias Complex

“…This is consistent with data from other studies that identified 22q11 duplications in approximately 3% of cases (Table 3). This is the most strongly associated genetic variation with BEEC, conferring a twelve-to-thirty-fold increased risk [55,56]. It is possible that the origin of the allele (paternal or maternal) that the duplication has arisen on, or the parent from whom the duplication has been inherited, alters the risk of BEEC.…”