Concordance analyses of twins with bladder exstrophy–epispadias complex suggest genetic etiology

Reutter, Heiko; Qi, Lihong; Gearhart, John P.; Boemers, Thomas M.; Ebert, A.; Rösch, Wolfgang; Ludwig, Michael; Boyadjiev, Simeon A.

doi:10.1002/ajmg.a.31975

Cited by 56 publications

(47 citation statements)

References 57 publications

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“…11,12,[14][15][16][17][18][19][20] included in our study, presented with the full picture of OEIS (Table 1) except for patient no. 13 showing no involvement of the central nervous system.…”

Section: Resultsmentioning

confidence: 98%

“…In this context, families with two or more members affected with ARM [8,11] and a 1.4% incidence of a positive family history in a series of 1,606 patients have been reported [10]. Likewise among BEEC families a 100-fold increased recurrence risk for siblings compared to the general population [12] and higher concordance rates among monozygotic twins compared to dizygotic twin pairs indicate a genetic aetiology [13]. However, due to the low prevalence of single and familial cases no genome-wide linkage or association study has been reported to date for non-syndromic forms.…”

Section: Introductionmentioning

confidence: 99%

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Investigation of FGF10 as a candidate gene in patients with anorectal malformations and exstrophy of the cloaca

et al. 2008

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The spectrum of anorectal malformations (ARM) comprises anal stenosis, ectopic anus, recto-urogenital fistula, persistent cloaca, multisystem VACTERL (VATER associations including cardiac and limb anomalies) associations, and exstrophy of the cloaca (CE). The latter also constitutes the most severe form of the bladder exstrophy epispadias complex. Since recent data revealed that fibroblast growth factor 10 (fgf-10) invalidation in mice resulted in a genetically reproducible urorectal defect, we considered FGF10 a suitable candidate gene for ARM and CE, as the protein seems to be involved in the development of this primary developmental field. A total of 20 patients (ten with ARM and VACTERL association, respectively, and ten with CE) were analysed for genomic mutations in the coding regions and exon-intron boundaries of FGF10. Aside from a common FGF10 variant no deviation from the wild-type sequence could be detected and data obtained is not supportive of FGF10 as a genetic cause of ARMs or CE in the patients investigated. Nonetheless, mutations in possibly further upstream located promoter regions and/or unknown regulatory sequences or non-coding regions cannot be excluded. Furthermore, it cannot be ruled out that other genes involved in the signalling pathway of FGF10 may contribute to the formation of these congenital malformations.

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“…11,12,[14][15][16][17][18][19][20] included in our study, presented with the full picture of OEIS (Table 1) except for patient no. 13 showing no involvement of the central nervous system.…”

Section: Resultsmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Investigation of FGF10 as a candidate gene in patients with anorectal malformations and exstrophy of the cloaca

et al. 2008

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“…So far, 56 twin pairs with CBE have been reported. Concordance rate among monozygotic twins is 5.6-fold higher than dizygotic twins [Reutter et al, 2007]. It is speculated that this entity is multi-factorial, affected by genetic susceptibility and environmental influence.…”

Section: Discussionmentioning

confidence: 99%

Is 1p36 deletion associated with anterior body wall defects?

Çöllü

Yüksel

Sirin

et al. 2016

American J of Med Genetics Pt A

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Epispadias and exstrophy of the cloaca, also known as OEIS complex (omphalocele, exstrophy, imperforate anus, spinal defects), respectively constitute the most benign and severe ends of the bladder exstrophy-epispadias complex (BEEC) spectrum. In 2009, El-Hattab et al. reported the first patient with OEIS complex associated with a chromosome 1p36 deletion. Here we report a second patient with 1p36 deletion who also has classic bladder exstrophy, supporting the possible role of genes in this region in the development of BEEC. The absence of omphalocele and imperforate anus in our patient places him toward classic bladder exstrophy while presence of spina bifida and the absence of coccyx suggest an overlap with OEIS complex. An additional differential diagnosis is the pentalogy of Cantrell in our patient as he also has a diaphragmatic hernia and an incomplete sternum. This is the second observation of a ventral midline birth defect in association with 1p36 deletion syndrome, following El-Hattab et al.'s report [2009]. The three genes (NOCL2, DVL1, and MMP23B) discussed as possible candidates are also among the deleted ones in our patient, supporting the possible role of these genes in BEEC spectrum. © 2016 Wiley Periodicals, Inc.

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“…While the etiology of BEEC remains unknown, strong evidence exists linking its development to genetic effects. The etiological association of genetic determinants is supported by the discrepant male to female ratio (7); a 400-fold increase of the recurrence risk for offsprings of affected individuals (8); observations of rare multiplex families (9); and much higher concordance rates (62% vs. 11%) among monozygotic as compared to dizygotic twins (10). Its non-Mendelian pattern of segregation and the incomplete concordance among MZ twins implies a complex trait model of inheritance.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide expression profiling of urinary bladder implicates desmosomal and cytoskeletal dysregulation in the bladder exstrophy-epispadias complex

Chen

Hur

et al. 2011

Int J Mol Med

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Abstract. The bladder exstrophy-epispadias complex (BEEC) represents a spectrum of urological abnormalities where part, or all, of the distal urinary tract fails to close during development, becoming exposed on the outer abdominal wall. While the etiology of BEEC remains unknown, strong evidence exists that genetic factors are implicated. To understand the pathways regulating embryonic bladder development and to identify high-probability BEEC candidate genes, we conducted a genome-wide expression profiling (GWEP) study using normal and exstrophic human urinary bladders and human and mouse embryologic bladderprecursor tissues. We identified 162 genes differentially expressed in both embryonic and postnatal human samples. Pathway analysis of these genes revealed 11 biological networks with top functions related to skeletal and muscular system development, cellular assembly and development, organ morphology, or connective tissue disorders. The two most down-regulated genes desmin (DES, fold-change, -74.7) and desmuslin (DMN, fold-change, -53.0) are involved in desmosome mediated cell-cell adhesion and cytoskeletal architecture. Intriguingly, the sixth most overexpressed gene was desmoplakin (DSP, fold-change, +48.8), the most abundant desmosomal protein. We found 30% of the candidate genes to be directly associated with desmosome structure/ function or cytoskeletal assembly, pointing to desmosomal and/or cytoskeletal deregulation as an etiologic factor for BEEC. Further findings indicate that p63, PERP, SYNPO2 and the Wnt pathway may also contribute to BEEC etiology. This study provides the first expression profile of urogenital genes during bladder development and points to the highprobability candidate genes for BEEC.

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Concordance analyses of twins with bladder exstrophy–epispadias complex suggest genetic etiology

Cited by 56 publications

References 57 publications

Investigation of FGF10 as a candidate gene in patients with anorectal malformations and exstrophy of the cloaca

Investigation of FGF10 as a candidate gene in patients with anorectal malformations and exstrophy of the cloaca

Is 1p36 deletion associated with anterior body wall defects?

Genome-wide expression profiling of urinary bladder implicates desmosomal and cytoskeletal dysregulation in the bladder exstrophy-epispadias complex

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