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

Molecular Genetics & Genomic Medicine

Anna Lindstrand¹  Daniel Nilsson¹  Vladana Vukojević²  Wolfgang Hofmeister³  Gundela Holmdahl⁴  Magnus Anderberg⁵  Jia Cao⁶  Johanna Lundin⁶  Izabella Baranowska Körberg⁶  Agneta Nordenskjöld⁶  Ellen Markljung⁶  Gillian Barker⁷ 

[1] Department of Clinical Genetics Karolinska University Hospital Stockholm Sweden;Department of Clinical Neuroscience, Center for Molecular Medicine Karolinska Institutet Stockholm Sweden;Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden;Department of Pediatric Surgery Sahlgrenska Academy Gothenburg Sweden;Department of Pediatric Surgery University Hospital Lund Lund Sweden;Department of Women’s and Children’s Health Karolinska Institutet Stockholm Sweden;Department of Women’s and Children’s Health Uppsala University Uppsala Sweden;

关键词: array‐CGH;    bladder exstrophy;    confocal microscopy;    exome sequencing;    fluorescence spectrometry;    LZTR1;   

DOI  :  10.1002/mgg3.666

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown