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.

Letter in honor to Marthe Gautier, honorary member of T21RS.

Dr. Marthe Gautier passed away the 30th of April 2022 at the age of 96. Her work showed for the first time the presence of a supernumerary chromosome in the cells from 9 individuals with “mongoloid” features as it was called in the 50ths. This discovery was the result of a year she spent in Harvard (1955-1956) to learn new technics of human cell culture (she co-authored in 1958 a paper in AMA Arch Pathol. on “Cells of human heart and aorta grown in tissue culture”), and of two years to implement these new techniques at the Trousseau hospital in the team of Dr Turpin who gave her a lab to “count the number of chromosomes in cells from individuals with Down syndrome”. Her discovery was confirmed by a paper published by Dr Patricia Jacob on the same year. This was the beginning of the genetic of chromosomal defects and a big step for the diagnosis of individuals with Down syndrome.

Last year, she was interviewed on the initial discovery of her scientific career: she was still revolted by remembering her surprise when she discovered that the results of her work were going to be published the next day (January 1959) with her name in second position. Feeling to be betrayed, she continued her career in pediatric cardiology, publishing on Tetralogy of Fallot and many other congenital cardiopathies. In a second part of her career, she became Research Director at INSERM and head of the lab “Anatomopathology of child hepatic diseases”. She received many awards in recognition of her important work.  Among them, the Winslow Price in 1971 and  the Monthyon Price of the French Academy of Sciences in 1975. In 2014, she was awarded the Grand Prize of Human Genetics from the French Society of Human Genetics and the French Federation of Human Genetics.  Dr. M Gautier was awarded the Legion of Honour, the highest French order of merit delivered by the President of France in 2014 and was promoted for her careers to the third level of “Commandeure de l’ordre national du Mérite” in 2018.