To contribute to the development of the transcription map of human chromosome 21 (HC21), we have used exon trapping to identify portions of HC21 genes. One trapped exon showed strong homology with members of the neural cell adhesion molecule (NCAM) family of genes from different species. We subsequently cloned the complete coding sequence from a human fetal brain cDNA library and determined its nucleotide sequence and predicted amino acid sequence. The predicted polypeptide of this novel NCAM2 gene contains 837 amino acids and shows 62% similarity to the NCAM homologs. It contains five immunoglobulin-like domains, two fibronectin type III domains, a transmembrane domain and a cytoplasmic domain. The gene is expressed most strongly in human adult and fetal brain. Using somatic cell hybrids, we mapped NCAM2 to 21q21, between markers D21S18 and D21S282. Radiation hybrid mapping localized this novel gene between polymorphic markers D21S1914 and D21S265. NCAMs are members of the immunoglobulin superfamily and are essential in the formation and maintenance of tissue structure. To date there are no candidate human disorders on HC21 that could be associated with mutations in NCAM2. In addition, the role of NCAM2 in the pathophysiology of Down syndrome is unknown. However, it is a good candidate for involvement in certain Down syndrome phenotypes because a slight overexpression of NCAMs increases many-fold the homotypic adhesion properties of cells.