A review of genetic factors contributing to the etiopathogenesis of anorectal malformations
Anorectal malformation (ARM) is a common congenital anomaly with a wide clinical spectrum. Recently, many genetic and molecular studies have been conducted worldwide highlighting the contribution of genetic factors in its etiology. We summarize the current literature on such genetic factors.
Materials and methods
Literature search was done using different combinations of terms related to genetics in anorectal malformations. From 2012 to June 2017, articles published in the English literature and studies conducted on human population were included.
Observations and results
A paradigm shift was observed from the earlier studies concentrating on genetic aberrations in specific pathways to genome wide arrays exploring single nucleotide polymorphisms (SNPs) and copy number variations (CNVs) in ARM patients. Rare CNVs (including 79 genes) and SNPs have been found to genetically contribute to ARM. Out of disrupted 79 genes one such putative gene is DKK4. Down regulation of CDX-1 gene has also been implicated in isolated ARM patients. In syndromic ARM de novo microdeletion at 17q12 and a few others have been identified.
Major genetic aberrations proposed in the pathogenesis of ARM affect members of the Wnt, Hox (homebox) genes, Sonic hedgehog (Shh) and Gli2, Bmp4, Fgf and CDX1 signalling pathways; probable targets of future molecular gene therapy.
KeywordsAnorectal malformations Genetic factors Etiology Copy number variations Chromosomal aberrations Single nucleotide polymorphisms
Anterior Intestinal portal
Caudal Intestinal portal
Copy number variation
Single nucleotide polymorphism
Compliance with ethical standards
Conflict of interest
No conflict of interest exists.
There is no financial support or funding to declare.
- 2.Fitzgerald MJT, Fitzgerald M (1994) Human Embryology. Bailliere Tindall, Philadelphia, pp 1–251Google Scholar
- 30.Dworschak GC, Draaken M, Marcelis C et al (2013) De novo 13q deletions in two patients with mild anorectal malformations as part of VATER/VACTERL and VATER/VACTERL-like association and analysis of EFNB2 in patients with anorectal malformations. Am J Med Genet A 161A:3035–3041CrossRefPubMedGoogle Scholar
- 38.Gurung N, Grosse G, Draaken M, Hilger AC, Nauman N, Müller A, Gembruch U, Merz WM, Reutter H, Ludwig M (2015) Mutations in PTF1A are not a common cause for human VATER/VACTERL association or neural tube defects mirroring Danforth’s short tail mouse. Mol Med Rep 12:1579–1583CrossRefPubMedGoogle Scholar
- 39.Stoll C, Alembik Y, Dott B, Roth MP (2007) Associated malformations in patients with anorectal anomalies. Eur J MedGenet 50:281–290Google Scholar
- 48.Kaufman RL, Hartman A, McAlister WH et al (1972) Family studies of congenital heart disease: a syndrome of hydrometrocolpos, proximal polydactyly and congenital heart disease. Birth Defects Orig Ser 8:85–8784Google Scholar