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

Lundin, Johanna; Markljung, Ellen; Baranowska Körberg, Izabella; Hofmeister, Wolfgang; Cao, Jia; Nilsson, Daniel; Holmdahl, Gundela; Barker, Gillian; Anderberg, Magnus LU and Vukojević, Vladana, et al. (2019) In Molecular Genetics and Genomic Medicine 7(6).
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... (More)

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.

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publication status
published
subject
keywords
array-CGH, bladder exstrophy, confocal microscopy, exome sequencing, fluorescence spectrometry, LZTR1, microduplication
in
Molecular Genetics and Genomic Medicine
volume
7
issue
6
publisher
John Wiley & Sons
external identifiers
  • scopus:85067292218
ISSN
2324-9269
DOI
10.1002/mgg3.666
language
English
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yes
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3c3248ea-2130-40b8-af2d-dff58bad5d96
date added to LUP
2019-07-01 09:42:38
date last changed
2019-07-30 05:05:36
@article{3c3248ea-2130-40b8-af2d-dff58bad5d96,
  abstract     = {<p>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<sup>−4</sup>). 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 Lztr1<sub>wt</sub> and Lztr1<sub>mut</sub>, indicating a potential functional effect of the LZTR1<sub>mut</sub>. 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.</p>},
  articleno    = {e666},
  author       = {Lundin, Johanna and Markljung, Ellen and Baranowska Körberg, Izabella and Hofmeister, Wolfgang and Cao, Jia and Nilsson, Daniel and Holmdahl, Gundela and Barker, Gillian and Anderberg, Magnus and Vukojević, Vladana and Lindstrand, Anna and Nordenskjöld, Agneta},
  issn         = {2324-9269},
  keyword      = {array-CGH,bladder exstrophy,confocal microscopy,exome sequencing,fluorescence spectrometry,LZTR1,microduplication},
  language     = {eng},
  number       = {6},
  publisher    = {John Wiley & Sons},
  series       = {Molecular Genetics and Genomic Medicine},
  title        = {Further support linking the 22q11.2 microduplication to an increased risk of bladder exstrophy and highlighting LZTR1 as a candidate gene},
  url          = {http://dx.doi.org/10.1002/mgg3.666},
  volume       = {7},
  year         = {2019},
}