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.

Genetic and nongenetic etiology of nonsyndromic anorectal malformations: A systematic review

“…The data seem to implicate a large number of different genes and loci, each with only limited support from other sources. Wong et al () also found 12 CNVs larger than 1 Mb in ostensibly isolated patients with ARM, including patients who were diagnosed with autism or who had CNVs that had previously been reported in patients with clear syndromic features. These CNVs had not been associated with ARM previously.…”

“…Few studies have been conducted using hypothesis‐generating methods to identify disease‐causing variants for ARM, such as genome‐wide association studies (GWAS). To date, only one small GWAS was performed in 175 patients with ARM, which did not reveal any common SNPs associated with ARM (Wong et al, ). However, a few recent genome‐wide CNV analyses provided potential candidate regions.…”

“…However, a few recent genome‐wide CNV analyses provided potential candidate regions. Wong et al () found an increase in rare deletions and duplications, which applied both to CNVs smaller and larger than 100 kb in size (Wong et al, ). How many of these rare CNVs were de novo or were inherited from unaffected parents is unclear.…”

The great divide: septation and malformation of the cloaca, and its implications for surgeons

“…Certain types of ARM such as recto-perineal fistula and recto-vestibular fistula are also more common to run in families when compared to more complex malformations 27 . Recently a genome-wide copy number variation study indicates that ARM are genetically a heterogeneous disease but this study did not include cloaca anomalies 28 .…”

2q33.1q34 Deletion in a Girl with Brain Anomalies and Anorectal Malformation

“…An anteriorly displaced anus is an ARM, which is a relatively frequent defect of hindgut development with an estimated incidence of 1 in 5,000 live births [Wang et al, 2015] and a heterogeneous aetiology with a contribution of both genetic and environmental factors. Chromosome imbalances are found in 4.5-11% of the ARM patients, and anomalies in 17 different chromosomes have been associated with ARM [Marcelis et al, 2011;Wong et al, 2013]. However, none of the reported individuals with a deletion overlapping the region deleted in our patient has this defect.…”