Dataset Information

Gene network analysis of candidate loci for human anorectal malformations.

ABSTRACT: Anorectal malformations (ARMs) are birth defects that require surgery and carry significant chronic morbidity. Our earlier genome-wide copy number variation (CNV) study had provided a wealth of candidate loci. To find out whether these candidate loci are related to important developmental pathways, we have performed an extensive literature search coupled with the currently available bioinformatics tools. This has allowed us to assign both genic and non-genic CNVs to interrelated pathways known to govern the development of the anorectal region. We have linked 11 candidate genes to the WNT signalling pathway and 17 genes to the cytoskeletal network. Interestingly, candidate genes with similar functions are disrupted by the same type of CNV. The gene network we discovered provides evidence that rare mutations in different interrelated genes may lead to similar phenotypes, accounting for genetic heterogeneity in ARMs. Classification of patients according to the affected pathway and lesion type should eventually improve the diagnosis and the identification of common genes/molecules as therapeutic targets.

SUBMITTER: Wong EH

PROVIDER: S-EPMC3731316 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Gene network analysis of candidate loci for human anorectal malformations.

Wong Emily H M EH Ng Chun-Laam CL Lui Vincent Chi-Hang VC So Man-ting MT Cherny Stacey S SS Sham Pak-Chung PC Tam Paul Kwong-Hang PK Garcia-Barceló Maria-Mercè MM

PloS one 20130801 8

Anorectal malformations (ARMs) are birth defects that require surgery and carry significant chronic morbidity. Our earlier genome-wide copy number variation (CNV) study had provided a wealth of candidate loci. To find out whether these candidate loci are related to important developmental pathways, we have performed an extensive literature search coupled with the currently available bioinformatics tools. This has allowed us to assign both genic and non-genic CNVs to interrelated pathways known t ...[more]

PMID: 23936318

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Project description:ObjectiveAnorectal malformations (ARMs) are one of the commonest anomalies in neonates. Both laparoscopically assisted anorectal pull-through (LAARP) and posterior sagittal anorectoplasty (PSARP) can be used for the treatment of ARMs. The aim of this systematic review and meta-analysis is to compare these two approaches in terms of intraoperative and postoperative outcomes.MethodsMEDLINE, Embase, Web of Science and the Cochrane Library were searched from 2000 to August 2016. Both randomized and non-randomized studies, assessing LAARP and PSARP in pediatric patients with high/intermediate ARMs, were included. The primary outcome measures were operative time, length of hospital stay and total postoperative complications. The second outcome measures were rectal prolapse, anal stenosis, wound infection/dehiscence, anorectal manometry, Kelly's clinical score, and Krickenbeck classification. The quality of the randomized and non-randomized studies was assessed using the Cochrane Collaboration's Risk of Bias tool and Newcastle-Ottawa scale (NOS) respectively. The quality of evidence was assessed by GRADEpro.ResultsFrom 332 retrieved articles, 1, 1, and 8 of randomized control, prospective and retrospective studies, respectively, met the inclusion criteria. The randomized clinical trial was judged to be of low risk of bias, and the nine cohort studies were of moderate to high quality. 191 and 169 pediatric participants had undergone LAARP and PSARP, respectively. Shorter hospital stays, less wound infection/dehiscence, higher anal canal resting pressure, and a lower incidence of grade 2 or 3 constipation were obtained after LAARP compared with PSARP group values. Besides, the LAARP group had marginally less total postoperative complications. However, the result of operative time was inconclusive; meanwhile, there was no significant difference in rectal prolapse, anal stenosis, anorectal manometry, Kelly's clinical score and Krickenbeck classification.ConclusionFor pediatric patients with high/intermediate anorectal malformations, LAARP is a better option compared with PSARP. However, the quality of evidence was very low to moderate.

Project description:The patients with anorectal malformations (ARM) have been identified with specific and non-specific pathological changes. The present study was conducted with the aim to study histomorphological changes and various immunohistochemical (IHC) markers (calretinin, S-100, CD117) in intestinal wall specimens to assess neuronal dysfunction in ARM patients.Thirty children having ARM were included in our study. In all the cases, a representative biopsy was received. The tissue sections were processed and wax blocks were prepared. Various histopathological changes were examined on routine H&E. Representative sections were further subjected to IHC staining for ganglion cells (calretinin), interstitial cells of Cajal (CD117) and nerve bundles (S-100 protein). Descriptive variables were analyzed to assess neuronal dysfunction in cases of ARM. Chi-square was used to compare the categorical values. P-value <0.05 was accepted as statistically significant.Biopsies were studied for histological changes using H&E stain. The most frequently observed histological finding in mucosa was inflammation and congestion in 87% and 67% of cases respectively. Disrupted muscularis mucosa was observed in 60%, eroded mucosa in 57%, and hemorrhage in 40% of cases. Submucosal inflammation and congestion were most common finding observed in submucosa in 87% and 80% cases respectively. CD117 was used to demonstrate altered density and distribution of interstitial cells of Cajal (ICC) in cases of ARM. Majority of them belong to grade 2+ category (n=17, 57%) followed by grade 1+ (n=8, 17%) for ICC cells. Altered density and distribution of ICC was observed in ARM which was statistically significant (p=0.02).The malformed segments in ARM show various specific and non-specific histomorphological changes. Examination of H&E sections along with IHC stains evaluation can minimize need for repeated biopsies and unnecessary radical treatment. CD117 immunohistochemistry is reliable adjunctive test in evaluation of ICC in motility disorders of bowel. Calretinin is good marker for identification of ganglion cells. In ARM, density and distribution of ICCs is significantly altered which can explain postoperative dysmotility.

Dataset Information

Gene network analysis of candidate loci for human anorectal malformations.

Publications

Gene network analysis of candidate loci for human anorectal malformations.

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