Gene Network Analysis of Candidate Loci for Human Anorectal Malformations

Emily H M Wong,Paul Kwong-Hang Tam,Vincent Chi-Hang Lui,Man-Ting So,Maria-Mercè Garcia-Barceló,Chun-Laam Ng,Pak-Chung Sham,Stacey S Cherny,Reiner Albert Veitia

doi:10.1371/journal.pone.0069142

Emily H M Wong, Paul Kwong-Hang Tam + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0069142

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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.

Highlights

Anorectal malformations (ARMs, congenital obstruction of the anal opening) are among the most common birth defects requiring surgical treatment (2–5/10,000 live-births) and carry significant chronic morbidity
Given the complexity of molecular events that take place during embryonic stages, impairments in any gene members of the pathways controlling the development of the anorectal region could lead to ARMs, accounting for the genetic heterogeneity observed among patients
These copy number variation (CNV) were not reported in the 11,943 healthy individuals from the Database of Genomic Variants (DGV), nor were they found in our 868 control individuals

Summary

Introduction

Anorectal malformations (ARMs, congenital obstruction of the anal opening) are among the most common birth defects requiring surgical treatment (2–5/10,000 live-births) and carry significant chronic morbidity. There is a wide spectrum of defects that differ in terms of malformation severity (ranging from anal stenosis to persistent cloaca) and the presence of different associated congenital anomalies. As shown in the genome-wide copy number variation (CNV) study we published recently [1], rare CNVs (either genic or non-genic) private to individual patients are likely to underlie the phenotype. The CNVs identified differ among patients indicating that ARMs are genetically heterogeneous diseases. Given the complexity of molecular events that take place during embryonic stages, impairments in any gene members of the pathways controlling the development of the anorectal region could lead to ARMs (or even lethality), accounting for the genetic heterogeneity observed among patients. Relevant pathways reported so far in animal studies include WNT, BMP and SHH

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