Oligogenic Disease Jon F. Robinson and Nicholas Katsanis 7 J.F. Robinson McKusick-Nathans Institute of Genetic Medicine, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA N. Katsanis () Wilmer Eye Institute, Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA e-mail: katsanis@jhmi.edu M.R. Speicher et al. (eds.), Vogel and Motulsky’s Human Genetics: Problems and Approaches, DOI 10.1007/978-3-540-37654-5_7, © Springer-Verlag Berlin Heidelberg 2010 Abstract One of the primary goals of human and medical genetics is to assign predictive value to the genotype – that is to say, to use genetic information to assist in the diagnosis and management of disease. Recent work, originating primarily from disorders thought to be traditionally inherited in a Mendelian fashion, have blurred the boundaries between allele causality in monogenic and complex disease. Studies on genetic variation in disease are now revealing that essentially no disorder is transmitted solely in a Mendelian fashion; rather there are always mul- tiple genetic and environmental factors that cause or modulate a disease phenotype. The focus of this chapter, oligogenic disorders, a term describing diseases caused by, or modulated by, a few genes, can provide a conceptual bridge between diseases classically considered monogenic and the poorly understood polygenic or complex disorders. The inheritance of alleles generally follows Mendelian laws of segregation and independent assortment. However, this axiom does not necessarily hold true when the segregation of disease traits is considered. Mendelian inheritance is founded on the notion that a trait (not exclusively a disease phenotype) is transmitted through a single locus; however, even in the most classic monogenic disorders the 1:1 or 3:1 Mendelian ratio of dominant to recessive phenotypes, respectively, cannot explain the breadth of phenotypic variation found in a clinical setting. Although environ- ment also plays a part, new research is showing that a large amount of the pheno- typic variation in “Mendelian” disorders is due to genetic interaction of several genes (Nat Rev Genet 3:779–789, 2002). In that context, most, if not all, disorders should be considered multifactorial; and the main reason they are Mendelized is that the majority of the phenotype can be attributed to variation/mutations at a single locus. 243