Pheochromocytomas are catecholamine-secreting tumors that result from mutations of several genes as components of distinct autosomal dominant disorders. However, familial occurrences of pheochromocytoma without an identifiable mutation support the existence of additional susceptibility loci. This study describes a novel familial pheochromocytoma syndrome linked to chromosomes 2 and 16 through a digenic recessive inheritance. These loci were identified by integration of two-locus linkage analysis, transcription profiling, and genome-wide single-nucleotide polymorphism (SNP)-based copy number mapping. Higher LOD scores were obtained for autosomal recessive (AR) compared to autosomal dominant (AD) model (Chromosome 2 results are show on left panel). SNP-based copy number analysis of chromosome 2 revealed recurrent loss of one copy of 2q with retention of the two normal copies of 2p (Right panel), as indicated by color intensity of normal compared with corresponding tumor samples (T). Average copy number along chromosome 2 is shown on the far right. The 2q target locus was narrowed down further by identification of additional pheochromocytomas with a similar genetic and transcription pattern. These findings provide evidence for novel susceptibility loci for pheochromocytoma and add a recessive digenic trait to the increasingly broad genetic heterogeneity of these tumors. Similarly complex traits may also be involved in other familial cancer syndromes. For details, see the article by Dahia et al. on page 9651 of this issue.