Interestingly, the patient phenotypes for the SHFM4 (only limb malformation), R227Q (mild EEC phenotype) and R298Q/G (no orofacial clefting) mutations is milder than for other ELA mutations that completely impair DNA binding, suggesting a correlation between residual DNA binding and severity of the phenotype. This evidence concerns the gene APELA and exstrophy-epispadias complex.