Genotype to phenotype-discovery and characterization of novel genomic disorders in a genotype-first era

Recent advances in technology for detecting copy number changes have enabled genome-wide detection of submicroscopic deletions and duplications. As these technologies are applied to large cohorts of patients with diverse phenotypes, novel genomic disorders are defined by a common genotype (deletion or duplication) rather than a common phenotype. The discovery of new genomic disorders using this genotype-first approach has increased dramatically, and several recently described recurrent rearrangements are associated with a surprisingly wide range of phenotypes. This review will discuss the importance of genomic architecture for generating recurrent rearrangements, implications of the genotype-first approach for medical genetics, and features of several new genomic disorders with highly variable phenotypes. Genet Med 2009:11(12):836-842.