History of Down syndrome research

This section devoted to The History of Down syndrome reveals the field’s evolution to present day. The work of pioneers has produced vital knowledge about trisomy 21 that is advancing today’s science and improving health outcomes.

Charles Epstein, a pioneer in Down syndrome research

“The science is finally catching up to the clinic.”

Dr. Charles Epstein, a UC San Francisco medical geneticist who studied Down syndrome and pioneered genetic counseling for families with affected children. His major research interests were in the genetics of early embryonic development, the pathogenesis of Down syndrome, genetic approaches to the study of free radical defense mechanisms, and aging. He hypothesized in the early 1970s that the abnormalities found in Down syndrome were due to an increased dosage of critical genes on chromosome 21. His dosage hypothesis was not the favored model at the time but has proven correct.

Charles Epstein

Sago H; Carlson EJ; Smith DJ; Rubin EM; Crnic LS; Huang TT; Epstein CJ. 2000. Genetic dissection of region associated with behavioral abnormalities in mouse models for Down syndrome. Pediatr Res 48(5):606-13.


He investigated one of the first genes identified on human chromosome 21, the interferon-alpha receptor gene (IFNAR1) and also the role of SOD1 and other homologs in free radical metabolism in aging. He decided to use the mouse as a model when starting his own lab to study early preimplantation mouse development and made important discoveries regarding the timing of initiation of X chromosome inactivation. These studies convinced him of the power of using a mammalian model such as the mouse for studying human genetic diseases, and several created mouse models relevant to the field.

He was also one of the first to formulate the conception that birth defects are caused by mutations in genes that act as pathways—inborn errors of development—similar to biochemical pathways. These examples—the study of human diseases such as Down syndrome with mouse models and the concept of inborn errors of development—also illustrate the integration of the basic principles of human genetic diseases with clinical genetics that was a hallmark of Charle’s contribution to the field and was a major motivating force in his research. He was the recipient of the two major awards of The American Society of Human Genetics (ASHG) in addition to serving as its President (1996) and as the editor of the Society’s journal (1987–1993). As he noted in his McKusick Leadership Award address, “The science is finally catching up to the clinic.”

Charles Epstein died on February 15, 2011, at the age of 77, after a year-long battle with pancreatic cancer.