Mendelian, non-Mendelian, multigenic inheritance, and epigenetics

Genetic variation has a contributory role in the biological perturbations that underlie the pathophysiology of much of human disease. It is now recognized that over 80% of all human genes are expressed in the nervous system, making neurogenetic disease phenotypes quite common. In this chapter, we review the modes of inheritance that can be observed in various human neurologic and psychiatric disease: Mendelian disorders, wherein mutations in a single disease-causing gene can result in a disease phenotype; non-Mendelian disorders, exemplified by mitochondrial inheritance, uniparental disomy and imprinting; multifactorial inheritance and complex traits, where interactions between various genes and environment are crucial to manifestation of a disease phenotype; and epigenetics, involving control of gene expression and gene-gene or gene-environment interactions. Emphasis is placed on clinical examples of genetic mechanisms, as well as on molecular methods used to identify genetic and genomic variability and mutations underlying neurogenetic phenotypes.