The Consequences of Abnormal Gene Dosage: Lessons from Chromosome 18

Accurate interpretation of genomic copy number variation (CNV) remains a challenge and has important consequences for both congenital and late-onset disease. Hemizygosity dosage characterization of the genes on chromosome 18 reveals a spectrum of outcomes ranging from no clinical effect, to risk factors for disease, to both low- and high-penetrance disease. These data are important for accurate and predictive clinical management. Additionally, the potential mechanisms of reduced penetrance due to dosage compensation are discussed as a key to understanding avenues for potential treatment. This review describes the chromosome 18 findings, and discusses the molecular mechanisms that allow haploinsufficiency, reduced penetrance, and dosage compensation. Abnormalities of gene dosage result in a wide number of effects ranging from being causal for disease to acting as a risk factor or having no clinical effect.Those affects may manifest congenitally or later in life.Reduced penetrance for any of the effects is a common finding and is an essential element of the clinical interpretation of genomic copy number variation.Understanding the mechanisms underlying reduced penetrance due to dosage compensation could provide important insight into potential treatment strategies for people with chromosome abnormalities.