BMP4 and WIF1 expression in mother–child pairs in relation to anorectal malformations and maternal reproductive history

Anorectal malformations (ARM) result from disrupted embryonic hindgut development, with both genetic and environmental factors contributing to disease pathogenesis. However, the relationships among maternal molecular alterations, reproductive history, and offspring gene expression remain poorly understood. This hospital-based case–control study evaluated BMP4 and WIF1 expression in peripheral blood from 182 biological mother–child pairs, comprising 83 children with ARM and 99 controls. Gene expression was quantified by quantitative real-time PCR and expressed as ΔCt, with 2⁻ΔΔCt used to describe relative expression. Consanguineous marriage was more frequent among mothers of children with ARM than controls (67.5% vs. 40.4%; odds ratio 3.06, 95% CI 1.66–5.63) and was included as a covariate in adjusted analyses. Children with ARM showed markedly reduced BMP4 expression compared with controls (0.44-fold, 95% CI 0.33–0.59), a difference unaffected by adjustment for consanguinity; BMP4 expression was similarly, though more modestly, reduced in their mothers (0.77-fold, 95% CI 0.63–0.95). Child WIF1 expression did not differ between groups, and evidence for altered maternal WIF1 expression was inconclusive. In multivariable regression, ARM status was the only independent predictor of child BMP4 ΔCt (B = 1.24, 95% CI 0.77–1.72, P < 0.001). Maternal miscarriage history significantly moderated the association between ARM status and child WIF1 ΔCt (FDR-adjusted P = 0.001 for miscarriage group; P = 0.004 for recurrent miscarriage). These findings support an association between reduced BMP4 expression and ARM in both children and their mothers and suggest that maternal reproductive history may modify child WIF1 expression. Prospective and functional studies are warranted to clarify the biological significance of these associations.