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.

Making chromosome abnormalities treatable conditions.

Individuals affected by the classic chromosome deletion syndromes which were first identified at the beginning of the genetic age, are now positioned to benefit from genomic advances. This issue highlights five of these conditions (4p-, 5p-, 11q-, 18p-, and 18q-). It focuses on the increased in understanding of the molecular underpinnings and envisions how these can be transformed into effective treatments. While it is scientifically exciting to see the phenotypic manifestations of hemizygosity being increasingly understood at the molecular and cellular level, it is even more amazing to consider that we are now on the road to making chromosome abnormalities treatable conditions.