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Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations.

ABSTRACT: INTRODUCTION:Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, assuming a multifactorial model. METHODS:We analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina HumanExome Beadchip array, which contains >240,000 rare and low-frequency coding variants. GenomeStudio clustering and calling was followed by re-calling of 'no-calls' using zCall for patients and controls simultaneously. Single variant and gene-based analyses were performed to identify statistically significant associations, applying Bonferroni correction. Following an extra quality control step, candidate variants were selected for validation using Sanger sequencing. RESULTS:When we applied a MAF of ?1.0%, no variants or genes showed statistically significant associations with ARM. Using a MAF cut-off at 0.4%, 13 variants initially reached statistical significance, but had to be discarded upon further inspection: ten variants represented calling errors of the software, while the minor alleles of the remaining three variants were not confirmed by Sanger sequencing. CONCLUSION:Our results show that rare and low-frequency coding variants with large effect sizes, present on the exome chip do not contribute to ARM etiology.

SUBMITTER: van de Putte R

PROVIDER: S-EPMC6538182 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations.

van de Putte Romy R Wijers Charlotte H W CHW Reutter Heiko H Vermeulen Sita H SH Marcelis Carlo L M CLM Brosens Erwin E Broens Paul M A PMA Homberg Markus M Ludwig Michael M Jenetzky Ekkehart E Zwink Nadine N Sloots Cornelius E J CEJ de Klein Annelies A Brooks Alice S AS Hofstra Robert M W RMW Holsink Sophie A C SAC van der Zanden Loes F M LFM Galesloot Tessel E TE Tam Paul Kwong-Hang PK Steehouwer Marloes M Acuna-Hidalgo Rocio R Vorst Maartje van de MV Kiemeney Lambertus A LA Garcia-Barceló Maria-Mercè MM de Blaauw Ivo I Brunner Han G HG Roeleveld Nel N van Rooij Iris A L M IALM

PloS one 20190528 5

<h4>Introduction</h4>Anorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, assuming a multifactorial model.<h4>Methods</h4>We analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina HumanExome Beadchip array, which con ...[more]

PMID: 31136621

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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

Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations.

Publications

Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations.

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