Proteomics is a powerful tool for evaluating differential protein expression comparing hundreds of proteins simultaneously. In the current study we performed "gene hunting" at the protein level and identified and quantified 10 protein spots in control and Down syndrome (DS) fetal brains. Using two-dimensional (2-D) electrophoresis of fetal brain proteins with subsequent MALDI-identification and quantification with specific software, we identified a series of poorly known proteins, in part hypothetical and orphans or poorly documented proteins. Hypothetical protein DKFZp564D177.1-human (fragment), one of these proteins was identified in fetal brain and was significantly decreased in DS (0.61+/-0.44, n = 7) compared to controls (3.43+/-1.83, n = 7). Septin 6, previously shown to be associated with synaptic vesicles, was present in all of 7 controls, but only in 1 out of 6 DS brains. We suggest that decreased protein levels of hypothetical protein DKFZp564D177.1-human (fragment) and lower prevalence of septin 6 could be involved in the maldevelopment of fetal DS brains. The other 8 proteins (WD repeat protein 1, novel protein highly similar to septin 2 homolog, septin 5, septin 2, DJ37E16.5 (novel protein similar to nitrophenylphosphatases from various organism), hypothetical 30.2 kDa protein, neuronal protein NP25, and DC7 protein (vacuolar sorting protein 29)) were comparable between controls and DS but could be identified in fetal and DS cortex, thus proposing them as tentative brain proteins.