Background: Significant advancement in the identification of genetic mutations and molecular pathways underlying Mendelian neurologic disorders was accomplished by using the methods of linkage, gene cloning, sequencing, mutation, and functional analyses, in the 1990s. Subsequently, the Human Genome Project defined the entire sequence of the genome providing reference for any pathologic condition, and identified single nucleotide polymorphisms as a means for whole genome association studies and linkage disequilibrium mapping in common, complex trait diseases. Simultaneously, data also emerged describing the structural chromosomal variations, and it became increasingly recognized that in addition to the more traditional mutation types, gene copy number variations (CNVs) contribute to normal variability in human phenotypes and may underlie the development of diseases with Mendelian inheritance, complex trait, or sporadic presentation.
Review summary: Here we describe the occurrence of CNVs in the human genome, and discuss their importance in health and disease. Targeting the practicing neurologist, we review the presently known CNVs with pathogenic significance in common neurologic disorders, and highlight new research directions in complex trait diseases.
Conclusions: The role of chromosomal structural variations in the pathogenesis of neurologic disorders is increasingly recognized. Available data may only capture a small subgroup of conditions related to these recently discovered genetic variations. The ongoing genome studies are expected to reveal structural chromosomal alterations as an underlying cause of many as yet poorly understood common diseases. New challenges include defining chromosomal break points, evaluating biologic consequences of gene dosage effect, and using molecular genetics for personalized therapeutic intervention. This survey of the CNV literature was closed in September 2008.