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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
Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden;Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden.
Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden.
Karolinska Inst, Dept Mol Med & Surg, Stockholm, Sweden.
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2019 (English)In: Molecular Genetics & Genomic Medicine, ISSN 2324-9269, Vol. 7, no 6, article id UNSP e666Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2019. Vol. 7, no 6, article id UNSP e666
Keywords [en]
array-CGH, bladder exstrophy, confocal microscopy, exome sequencing, fluorescence spectrometry, LZTR1, microduplication
National Category
Medical Genetics
Identifiers
URN: urn:nbn:se:uu:diva-392055DOI: 10.1002/mgg3.666ISI: 000476745400018PubMedID: 31044557OAI: oai:DiVA.org:uu-392055DiVA, id: diva2:1349837
Funder
Swedish Research Council, K2012-64X-14506-10-5Knut and Alice Wallenberg Foundation, KAW 2011.0218The Swedish Brain FoundationAvailable from: 2019-09-10 Created: 2019-09-10 Last updated: 2019-09-10Bibliographically approved

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