Carney complex (CC) is a familial multiple neoplasia and lentiginosis syndrome, transmitted in an autosomal dominant manner. It is the only familial form of cardiac and skin myxomas known, and is associated with endocrine neoplasms causing Cushing syndrome and acromegaly. We recently mapped the gene(s) responsible for CC on the short arm of chromosome 2 by linkage analysis of 11 North American kindreds (Stratakis et al. J.Clin. Invest. 97 (2): 1-7, 1996). Two additional kindreds (7 affected individuals) were recently recruited. Blood and tumor samples from patients and their family members were obtained. Patient-derived lymphoblastoid and tumor cell lines were established. Linkage analysis with microsatellite markers from the short arm of chromosome 2 (band 2p16) showed co-segregation with the disease locus with no new recombination events in one of the new families. Multipoint linkage analysis defined a region of approximately 4 cM, bordered by markers CA2 and D2S378, that is likely to contain the gene(s) associated with CC. Candidate genes in the proximity included the microsatellite stability-maintaining hMSH2 and hMSH6 genes, which, however, were excluded. The gene that codes for calcineurin (CALNB1) was also recently mapped to 2p16. After determining the intron-exon junctions of this gene, SSCP analysis and direct sequencing of its 5 exons did not reveal any abnormalities in 5 patients with CC from different families. Chromosome and microsatellite analysis of 9 tumors and tumor-derived cell lines indicated significant genomic, but not microsatellite instability, which was mostly present in telomeric regions. Since these and other tumors demonstrated genomic instability, and the hMSH2, hMSH6 and CALNB1 genes were excluded, we hypothesize that other, as yet unknown genes in this region are responsible for CC, whose function may be related to the preservation of chromosomal integrity and growth of dividing human cells. In order to identify the CC and other genes, we are constructing a detailed physical map of chromosome 2p16 employing YAC, BAC, PAC and P1 libraries. New CC families are collected for further refinement of the locus.