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.

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Journal PLoS ONE
van de Putte, R., Wijers, C.H.W, Reutter, H, Vermeulen, SH, Marcelis, CLM, Brosens, E, … de Rooij, I. (2019). Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations. PLoS ONE, 14(5). doi:10.1371/journal.pone.0217477